The Protein Acetylation Rheostat: Linking Autophagy and Senescence in Metabolic Disease

1. Introduction

Metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD/NAFLD), are characterized by chronic nutrient surplus and the progressive deterioration of tissue resilience (Hotamisligil, 2017). At the cellular level, these pathologies reflect a failure of two coupled stress-adaptive programs, such as autophagy and cellular senescence. These programs function as homeostatic engines, integrating nutrient signaling (via hubs such as mTORC1 and SIRT1) to maintain cellular quality control through lysosomal recycling and the removal of irreparable cells (Kitada & Koya, 2021; Lee et al., 2021). However, chronic overnutrition triggers a reciprocal ‘vicious cycle’ where impaired autophagic flux directly fuels the transition toward a persistent, pro-inflammatory senescence program. The resulting accumulation of damaged components and the SASP drive systemic insulin resistance and broader tissue dysfunction, including β-cell tissue failure (Chaib et al., 2026; Kitada & Koya, 2021). Consequently, the balance between these two processes has emerged as a central determinant of whether metabolic stress is resolved or progresses into long term or irreversible pathology (Kitada & Koya, 2021; Liu et al., 2020).

Emerging evidence identifies protein acetylation as a nutrient-sensitive integrator that coordinates the autophagy-senescence balance across metabolic tissues (Yinfeng Xu & Wei Wan, 2023; Yu et al., 2025). This regulatory layer functions as a molecular rheostat, where the availability of acetyl-CoA fuels lysine acetyltransferases (KATs, e.g., EP300/CBP) and NAD⁺ levels dictate sirtuin- mediated deacetylation. Through this metabolic coupling, acetylation controls autophagy at multiple checkpoints, ranging from the direct modification of core ATG proteins and ULK/Beclin-1 complexes to the transcriptional orchestration of lysosomal biogenesis (Yinfeng Xu & Wei Wan, 2023). Simultaneously, acetylation stabilizes the senescent state by driving enhancer remodeling and modulating the activity of non-histone effectors, including p53, NF-kB, and FOXO proteins (Sen et al., 2019; Xu et al., 2025). Under chronic metabolic stress, the depletion of NAD⁺ and subsequent loss of sirtuin activity trigger a shift toward pathological hyperacetylation. This imbalance suppresses autophagic flux while reinforcing pro-inflammatory chromatin landscapes, ultimately locking cells into a state of persistent damage accumulation and metabolic decline (Hwang et al., 2013; Palmer et al., 2022).

This review synthesizes the evidence for protein acetylation as a pivotal metabolic integrator coordinating autophagic flux and cellular senescence. We propose the “Acetylation Rheostat” hypothesis, which posits that cellular homeostasis is dictated by the relative availability of acetyl-CoA and NAD⁺. This metabolic state modulates the activity of the EP300-sirtuin axis, thereby determining the balance between homeostatic quality control and inflammatory remodeling. When this regulatory hub is skewed by chronic overnutrition, it triggers the ‘double blow’ of impaired clearance and persistent senescence that drive the progression of obesity, T2DM, and MASLD. This review establishes a comprehensive roadmap of the biochemical sensors of nutrient status before detailing the molecular toggle switches (e.g., p53, FOXO, mTORC1) that translate acetylation signals into cell-fate decisions. Finally, we examine these dynamics from a tissue-specific perspective and highlight therapeutic ‘rebalancing’ strategies aimed at restoring cellular resilience at its regulatory root, rather than merely treating its downstream pathological consequences.

2. The Metabolic Crisis: Autophagy Failure and Senescence Accumulation

2.1. Autophagy Failure in Metabolic Tissues

In metabolic tissues, autophagy acts as a core homeostatic engine that couples nutrient signaling, primarily via the AMPK-mTORC1 axis, to lysosomal recycling in order to sustain proteostasis, mitochondrial integrity, and lipid handling during feeding-fasting cycles. By sequestering damaged mitochondria (mitophagy) and other dysfunctional macromolecules into autophagosomes and clearing them via lysosomes, autophagic flux provides continuous cellular ‘housekeeping’, thereby protecting the insulin signaling network from chronic stress (Cao et al., 2021; Liu et al., 2023). Although autophagy is crucial for maintaining cellular homeostasis, autophagic efficiency declines with overnutrition, aging and metabolic derangements including obesity, insulin resistance, and T2DM, thereby amplifying metabolic stress and tissue dysfunction (Jakubek et al., 2024; Kitada & Koya, 2021; Raza, 2024). Further, the impairment of autophagy through the genetic loss of Atg7 or pharmacological inhibition disrupts adipose tissue mass and differentiation while enhancing pro-inflammatory cytokine expression. Consequent to the decline in autophagic flux, the accumulation of damaged and superfluous cargo raises reactive oxygen species (ROS) and amplifies pro-inflammatory signaling along with increasing NLRP3 inflammasome-linked inflammatory tone, leading to insulin resistance and tissue dysfunction (Biasizzo & Kopitar-Jerala, 2020).

However, compelling evidence indicates that enhancing autophagic flux can effectively ameliorate various metabolic diseases. In adipose tissue, autophagy serves as a protective mechanism that restrains obesity-associated fibrosis and maintains the functional integrity of visceral white adipose tissue by regulating tissue purine nucleoside metabolism (Piletic et al., 2025). Similarly, hepatic autophagy has emerged as a metabolic control node. For example, activation of melanocortin 3 receptor signaling has been shown to reduce adipose tissue lipid accumulation and restore body weight in obese mouse models via the regulation of hepatic autophagy (Patel et al., 2025). Mechanistic studies further demonstrate that GLP-1 receptor agonists can reduce hepatic steatosis by inducing autophagy through the AMPK/SIRT1 signaling pathway (Yu et al., 2025). Furthermore, preclinical research has expanded this concept to include TFEB-centered lysosomal- autophagy programs and metabolic intermediates. Examples include the Qigui Jiangzhi Formula, which improves MASLD via modulation of the AMPK/SIRT1-TFEB pathway (Zhang et al., 2025), and the use of aminobutyric acid to halt MASLD progression in mice by inducing autophagic flux (Felicianna et al., 2025). Consistent with these mechanistic pathways, research on autophagy emphasizes that it is not simply ‘bulk degradation’ mechanism, but a highly selective and flux-dependent pathway critical for adaptation to metabolic stress and the prevention of chronic disease development (Glick et al., 2010; Kitada & Koya, 2021; Lee et al., 2025; Tao et al., 2025).

2.2. Senescence Burden in Metabolic Disease

By contrast, cellular senescence contributes to metabolic homeostasis only when it is transient, such as during wound repair or tumor suppression. However, in metabolic disease, it frequently becomes persistent, causing durable growth arrest along with a SASP that drives inflammation, extracellular matrix remodeling, immune-cell recruitment, and insulin resistance (Palmer et al., 2022; Saliev & Singh, 2025; Spinelli et al., 2023). Recent evidence underscores the critical role of senescent cells in curtailing both health-span as well as lifespan. Their chronic accumulation is now recognized as a key driver of various pathologies, including metabolic dysfunction and accelerated aging syndromes (Chaib et al., 2026; Papatheodoridi et al., 2020; Suda et al., 2025). Research utilizing genetic and pharmacological senescent-cell clearance models has shown that reducing the senescent cell burden in obese mice effectively alleviates metabolic dysfunction, improves glucose homeostasis, and enhances overall longevity. For example, the selective clearance of p16^Ink4a+ senescent cells can mitigate systemic inflammation and improve glucose metabolism in obese mice (Suda et al., 2025). Similarly, in another study, senescent hepatocytes have been identified as central drivers of MASLD. therefore, eliminating these cells presents a promising therapeutic strategy for treating liver disease and its associated multi-organ complications (Du et al., 2025). Further, human atlas studies have revealed that while weight loss has the potential to reverse adipose senescence and improved metabolic remodeling, an “obesogenic epigenetic memory” can persist in these tissues, potentially leading to a rebound in metabolic dysfunction. Thus, elimination of such senescent cells represents a key therapeutic target to improve metabolic health (Hinte et al., 2024; Miranda et al., 2025). These insights further extend to skeletal muscle, where multi-omics profiling has identified Maraviroc as a potential senotherapeutic strategy to combat sarcopenia-associated loss of muscle mass and strength (Y. Li et al., 2025). Finally, a pivotal study showed that inhibition of TGFβ can hinder senescence transmission from liver to other organs, thereby preventing systemic multi-organ dysfunction; thus, providing powerful evidence that senescence is an active driver rather than a mere bystander in metabolic homeostasis (Kiourtis et al., 2024; Saliev & Singh, 2025).

2.3. Mechanistic Crosstalk Between Autophagy and Senescence

Mechanistically, metabolic stress initiates a ‘vicious cycle’ where autophagy failure acts as persistent pro-senescence signal which accelerates senescence, and the established senescent state further represses autophagic capacity. Impaired autophagy exacerbates mitochondrial dysfunction, amplifying ROS and DNA damage signaling that enforces senescence commitment (Figure 2). However, autophagy restoration at this stage can break this cycle and restore regenerative function in aged cells (Bahar et al., 2026; García-Prat et al., 2016; Rajendran et al., 2019). Once senescence is established, SASP-associated inflammatory signaling (often via NF-κB) can up-regulate autophagy inhibitors such as A20, Bcl-2/Bcl-xL while suppressing pro-autophagy mediators such as BNIP3 and JNK1, further reducing cellular clearance capacity and augmenting damage accumulation (Salminen et al., 2012). In addition, autophagy-dependent RNA splicing and translational rewiring during senescence actively direct inflammatory output, thereby perpetuating defective clearance and SASP maintenance (Kim et al., 2025). Moreover, the negative regulator of autophagy (Rubicon) rises with age to down-regulate autophagic flux, predisposing tissues to damage accumulation and senescence pressure (Nakamura et al., 2019). In parallel, senescence has been evidenced to robustly suppress mitophagy, locking cells into an elevated ROS and pro-inflammatory state that further perpetuates the SASP program (Chaib et al., 2026; Kelly et al., 2024; Suda et al., 2025).

These coupled failures of autophagy and senescence control suggest the existence of an upstream metabolic regulator, a “master switch”, that can orchestrate both mechanisms simultaneously. Under metabolic stress, changes in nutrient availability reshape intracellular acetyl-CoA and NAD⁺ pools, thereby shifting the balance between acetyltransferases and deacetylases. This places “protein acetylation” in a prime position to function as a nutrient-sensitive regulatory layer that links the metabolic state to the control of both autophagy and senescence (Keller & Nakamura, 2024; Xu et al., 2025). For instance, on one hand, chronic mTORC1 signaling activates p300, impairing autophagic quality control via the acetylation of core autophagic machinery, while; on the other hand acetylation-dependent chromatin remodeling, including p300-driven super-enhancer formation and BRD4 recruitment, stabilizes senescence and SASP transcription. Ultimately, it supports the view that a single regulatory layer, i.e., “protein acetylation”, is capable of pushing both arms of this metabolic ‘double blow’ in the same pathological direction (García-Prat et al., 2016; Ghosh, 2021; Tasdemir et al., 2016; Wan et al., 2017; Y. Xu & W. Wan, 2023).

3. Protein Acetylation: The Nutrient-Sensitive Sensor of Cellular Metabolic Status

3.1. Biochemical Foundation of Protein Acetylation

Protein acetylation predominantly occurs as N-terminal acetylation and lysine ε-N-acetylation, with lysine acetylation being the major reversible form regulating chromatin, metabolism, and signaling (Ali et al., 2018; Zhou & Cole, 2025). Lysine acetylation is a reversible post-translational modification (PTM), involving dynamically regulated addition of an acetyl group (CH3CO) to the ε-amino group of lysine residue. This modification neutralizes the positive charge of the lysine residue, which can significantly alter its protein conformation, chromatin accessibility, enzymatic activity, and molecular interactions. This process is enzymatically catalyzed by lysine acetyltransferase (KATs), such as p300/CBP; while the removal of acetyl groups is performed by deacetylases, including histone deacetylases (HDACs) and nicotinamide adenine dinucleotide NAD⁺-dependent sirtuins (Ali et al., 2018; Y. Xu & W. Wan, 2023; Yazıcı & McIntyre, 2025). For example, in mitochondria, the high concentration of acetyl-CoA, alkaline matrix pH and the higher density of reactive metabolites favor acetyl transfer reactions. Consequently, non-enzymatic protein acetylation represents the most prevalent post-translational modification in this organelle. In this environment, sirtuins (such as SIRT3) function as a key ‘deacetylation repair’ system, counterbalancing the non-enzymatic accumulation of acetyl groups to preserve mitochondrial oxidative metabolism and quality control. This biochemical foundation positions acetylation as a vital upstream regulator that integrates nutrient availability with cellular stress-adaptive responses (Hosp et al., 2017; M. Q. Li et al., 2025; Shimazu et al., 2025).

3.2. Metabolic Dependence of Acetylation and Compartmentalized Acetyl-CoA/NAD+ Pools

Having outlined the biochemical basis of lysine acetylation, it is also important to its intrinsic link to cellular metabolism. This dependency arises because the activities of the modifying enzymes are governed by the availability of metabolic substrates and cofactors. Specifically, KAT activity depends on local acetyl-CoA availability, while sirtuin-regulated deacetylation requires NAD⁺_. Therefore, alternations in nutrient supply, mitochondrial function, as well as redox status can directly shift the local and global acetylation tone, allowing this modification to serve as a versatile metabolic sensor (Shi & Tu, 2015; Sivanand et al., 2018; Wellen et al., 2009).

A defining reason for acetylation being metabolically informative and versatile is that acetyl-CoA is compartmentalized into separate, functionally distinct pools. The mitochondrial acetyl-CoA pool (derived primarily from β-oxidation and the pyruvate dehydrogenase complex) is regulated independently and serves explicit local metabolic functions and is not freely interchangeable with nuclear/cytosolic pools. Despite the permeability of nuclear pores to acetyl-CoA, recent metabolic evidence suggests that nuclear and cytosolic acetyl-CoA pools are largely distinct and gate specific local acetylation programs (Guertin & Wellen, 2023; Sivanand et al., 2018). The nuclear-cytosolic acetyl-CoA is generated from two canonical precursors; citrate, via ATP-citrate lyase (ACLY), and acetate, via acyl-CoA synthetase short-chain 2 (ACSS2). Moreover, alternative shuttling routes, such as acetyl carnitine-associated transfer, help sustain nuclear and cytosolic acetylation when primary sources are constrained (Izzo et al., 2023).

Such principles are especially relevant in metabolic diseases, where these compartmentalized dynamics allow acetylation to function as a metabolic master switch that simultaneously tunes autophagy and senescence to maintain metabolic homeostasis (Morales-Tarré et al., 2021; Wang & Lei, 2018). The same metabolites that are sensitive to nutrient status, such as acetyl-CoA and NAD⁺, control the opposing activities of EP300/CBP and sirtuins, which in turn regulate both autophagic machinery and senescence programs. For instance, under nutrient-rich conditions with high acetyl-CoA levels, activated EP300 acetylates autophagy core ATG proteins, impairing autophagic flux. Simultaneously, up-regulated EP300 activity promotes a hyperacetylated enhancer landscape that boosts the expression of senescence-associated genes. Conversely, during starvation or NAD⁺-favored conditions, sirtuin-mediated deacetylation restores autophagic competence while restraining pro-senescent chromatin remodeling (Lee et al., 2008; Lee & Finkel, 2009; Mariño et al., 2014; Sen et al., 2019). In brief, acetylation is uniquely positioned to convert the cellular metabolic state into the coordinated regulation of intracellular quality control and cell-fate remodeling, and thus changes in the acetylation state can shift both processes simultaneously (Eisenberg et al., 2009; Kang & Elledge, 2016; Lee et al., 2021; Sun et al., 2021; Xu et al., 2025).

4. The Molecular Toggle Switch: Reciprocal Regulation of Pathological Programs

Having established the biochemical basis of acetylation, we now turn to its role in regulating autophagy and senescence simultaneously. Acetylation is not merely a downstream marker of metabolic stress; it functions as a bidirectional molecular toggle that converts changes in acetyl-CoA and NAD⁺ availability into coordinated shifts in autophagic flux and senescence programs. In metabolic diseases, prolonged nutrient surplus can bias cells towards KAT-driven acetylation and away from sirtuin-mediated deacetylation, leading to simultaneous autophagic suppression and senescence stabilization, consequently driving metabolic disease progression (Lee et al., 2008; Lee & Finkel, 2009; Mariño et al., 2014; Rajendran et al., 2019; Sen et al., 2019) (Figure 1).

Figure 1. Acetylation rheostat model linking nutrient status to reciprocal regulation of autophagy and senescence in metabolic diseases. Nutrient-sensitive acetylation acts as a rheostat that reciprocally regulates autophagy and senescence. In nutrient-rich states, increased acetyl-CoA and mTORC1 activity favors p300-dependent acetylation, suppressing autophagic flux and promoting senescence-associated chromatin remodeling, p16/p21 induction, and SASP expression. While, in nutrient scarce states, increased NAD⁺ and reduced mTORC1 activity favors sirtuin-mediated deacetylation, restoring autophagy and restraining senescence. Chronic nutrient excess shifts this balance towards impaired cellular quality control and persistent inflammatory remodeling in metabolic disease.

Figure 1. Acetylation rheostat model linking nutrient status to reciprocal regulation of autophagy and senescence in metabolic diseases. Nutrient-sensitive acetylation acts as a rheostat that reciprocally regulates autophagy and senescence. In nutrient-rich states, increased acetyl-CoA and mTORC1 activity favors p300-dependent acetylation, suppressing autophagic flux and promoting senescence-associated chromatin remodeling, p16/p21 induction, and SASP expression. While, in nutrient scarce states, increased NAD⁺ and reduced mTORC1 activity favors sirtuin-mediated deacetylation, restoring autophagy and restraining senescence. Chronic nutrient excess shifts this balance towards impaired cellular quality control and persistent inflammatory remodeling in metabolic disease.

Figure 2. Mitochondrial acetylation: Mitophagy mismatch links nutrient surplus to senescence and metabolic disease progression. Nutrient surplus /metabolic stress elevates mitochondrial acetylation pressure, while weakening SIRT3-dependent deacetylation, promoting mitochondrial hyperacetylation, and ROS generation. It leads to mitochondrial dysfunction and activation of senescence-associated signaling. Simultaneously, mTORC1 activation suppresses mitophagy via acetylation of core autophagic machinery, reducing clearance capacity. The resulting mismatch between mitochondrial damage and mitochondrial clearance drives damaged mitochondria accumulation, inflammatory and senescence associated signaling, and metabolic disease progression. Protective NAD⁺/SIRT3-dependent counter-regulation limits these effects by restoring mitochondrial quality control.

Figure 2. Mitochondrial acetylation: Mitophagy mismatch links nutrient surplus to senescence and metabolic disease progression. Nutrient surplus /metabolic stress elevates mitochondrial acetylation pressure, while weakening SIRT3-dependent deacetylation, promoting mitochondrial hyperacetylation, and ROS generation. It leads to mitochondrial dysfunction and activation of senescence-associated signaling. Simultaneously, mTORC1 activation suppresses mitophagy via acetylation of core autophagic machinery, reducing clearance capacity. The resulting mismatch between mitochondrial damage and mitochondrial clearance drives damaged mitochondria accumulation, inflammatory and senescence associated signaling, and metabolic disease progression. Protective NAD⁺/SIRT3-dependent counter-regulation limits these effects by restoring mitochondrial quality control.

4.1. The mTORC1-p300 Integration Hub: Feeding-Induced Autophagy Suppression and Senescence Stabilization

Upstream nutrient sensing is most directly regulated by acetylation-linked control via mTORC1-p300 axis, which couples the fed states to the suppression of autophagy and enhanced lipogenic programs. Under nutrient-rich conditions, such as high amino acid or insulin levels, mTORC1 is activated and directly phosphorylates p300 at several C-terminal serine residues, thereby stimulating its acetyltransferase activity. Activated p300/CBP suppresses autophagy at both early and late checkpoints. Specifically, p300 acetylates core autophagy proteins, such as ATG5, ATG7, ATG8/LC3, and ATG12, sequestering them in the nucleus and preventing their participation in cytoplasmic autophagosome formation (Lee & Finkel, 2009; Wu et al., 2021). Furthermore, p300-mediated acetylation of Beclin-1 (at K430/K437) promotes the recruitment of Rubicon, which constrains autophagosome maturation and endocytic trafficking. This mechanism ultimately lowers net autophagic flux even in the presence of initiation signals (Sun et al., 2015; Y. Xu & W. Wan, 2023; Yazıcı & McIntyre, 2025). Thus, consistent with this model, pharmacological inhibition of p300/CBP has been shown to rapidly reduce lipogenesis in liver and adipose tissue, suppress hepatic gluconeogenesis, and alleviate insulin resistance, positioning p300 as a promising therapeutic target for treating autophagy-related metabolic disorders (Ansari et al., 2023; Y. Xu & W. Wan, 2023; Zhou et al., 2020) (Figure 3).

In parallel, p300 activity is crucial during senescence entry, acting as a primary driver by inducing de novo super enhancers (SEs) formation and promoting the hyper-acetylated chromatin state that establishes the senescence-specific gene expression program. For example, during replicative senescence, p300 reshapes large regions of the non-coding genome into these SEs to sustain the expression of senescence associated genes, including cell cycle inhibitors like p16 and p21 (Sen et al., 2019; Yu et al., 2025). While p300 initiates this state, the maintenance stage relies on the downstream recruitment of BRD4, an acetyl-lysine reader that binds to p300-induced acetylation marks to sustain transcriptional activity. This creates a positive feedback loop that strengthens the senescent phenotype. Mechanistically, BRD4 recruitment to newly activated SEs near SASP genes facilitates robust pro-inflammatory transcription and paracrine signaling, a mechanism that drives persistent inflammation in MASLD, obesity and T2DM (Di Giorgio et al., 2021; Tasdemir et al., 2016). Moreover, recent literature underscores the pivotal role of BRD4 as a key epigenetic reader that governs the maintenance of SASP and broader aging-associated transcriptional programs (Sun et al., 2024; Wang et al., 2024). Recent work further supports p300 as an epigenetic driver of premature senescence and highlights that the stable growth arrest and inflammatory remodeling associated with stress-induced senescence can be effectively delayed or mitigated through the pharmacological inhibition of p300 (Di Fede et al., 2025).

In conclusion, in metabolic disease, the chronic activation of mTORC1 pushes the system via p300 to simultaneously repress autophagic quality control and lock in senescence and SASP programs, creating a pathological feed-forward loop of inflammatory signaling, lipid accumulation, and tissue dysfunction (Sen et al., 2019; Son et al., 2024; Sun et al., 2015; Wan et al., 2017) (Figure 1).

4.2. Acetylation Modification of Core Regulatory Hubs: p53, FOXO, and NF-κB

Beyond the regulation of the upstream integration hub, acetylation also governs cell fate through the modification of various other core regulatory hubs, specifically key transcription factors, including p53, FOXO, and NF-κB. Once stress and nutrient signals are detected, the acetylation-dependent regulation of these “gatekeeping” factors jointly determines whether a cell undergoes stress adaptation via autophagy or transitions into durable senescence characterized by inflammatory remodeling (Son et al., 2025).

Increased acetylation of p53 significantly boosts its transcriptional activity. For example, the acetylation of p53 at Lys120 by MOZ leads to p21/p16 induction and pushing the cells towards stable growth arrest (Hu et al., 2023). However, when stress is intermittent, deacetylases such as SIRT1 act as a negative regulators by deacetylating p53 at Lys382, thereby restraining its transcriptional output and reducing the probability of permanent arrest (Yu et al., 2025). This balance is critical in metabolic disease, where nutrient surplus often increases acetylation pressure while suppressing deacetylation capacity. This environment makes p53-regulated arrest more robust and harder to resolve, facilitating chronic tissue dysfunction (Vaziri et al., 2001; Wang et al., 2023; Zhang et al., 2017). Interestingly, dietary interventions such as glucose restriction (via carbohydrate-free dietary regimens) have been shown to induce a specific form of p53 acetylation that routes the protein for degradation via autophagy, highlighting a potential therapeutic mechanism to clear pro-senescent factors (Rodriguez et al., 2012).

NF-κB functions as the primary transcriptional engine for SASP chemokines/cytokines, with its output becoming specifically “hard-wired” through enhancer remodeling during the progression of senescence. Acetylation of the p65 subunit of NF-κB at Lys310 significantly enhances its transcriptional activity, which is essential for the maintenance of the SASP state. Conversely, the deacetylation of p65 by SIRT1 inhibits this process, effectively reducing the production of potent pro-inflammatory cytokines, such as IL-6 and IL-8 (Yeung et al., 2004; Yu et al., 2025). Mechanistically, this acetylation event enables the recruitment of acetyl-lysine reader BRD4 to newly activated super-enhancers adjacent to SASP genes. This BRD4 recruitment is significantly involved in SASP regulation and downstream paracrine signaling. While the activation of NF-κB initiates early in the stress response, BRD4-mediated super-enhancer control is predominantly critical for the long-term maintenance of senescence and amplification of SASP. This epigenetic mechanism represents a major disease-driving component in conditions such as MASLD, obesity and T2DM (Brown et al., 2014; Tasdemir et al., 2016). Furthermore comparative studies show that such enhanced NF-κB signaling during aging and cellular senescence actively suppresses cellular quality control by up-regulating the expression of autophagy inhibitors, (e.g., A20, and Bcl-2/Bcl-xL) and repressing the essential autophagy activators, such as BNIP3, JNK1, and ROS (Salminen et al., 2012).

Beyond p53 and NF-κB, the FOXO transcription factor family (notably FOXO1 and FOXO3a) serves as another major regulatory hub whose function is tightly governed by acetylation. For example, the acetylation of FOXO1 or FOXO3a transcription factors inhibits their transcriptional activity and diminishes the cellular antioxidant defenses, thereby driving cell fate towards senescence. Conversely, oxidative stress-induced deacetylation enhances FOXO activity, promoting mitochondrial resilience and the expression of autophagy-related genes while simultaneously suppressing the cellular senescence program (Gupta et al., 2025; Kuo et al., 2025; Zhang et al., 2013). By integrating with sirtuin signaling and mitochondrial status, the FOXO family functions as a critical ‘bridge-hub’ that coordinates the reciprocal relationship between autophagy and senescence.

4.3. Organelle-Specific Acetylation Regulation of Mitophagy, ROS, and Senescence

Beyond the nucleus and cytosol, mitochondrial acetylation establishes a critical “damage loa” that escalates the demand for autophagy/mitophagy, the selective autophagic degradation of mitochondria, while simultaneously fueling senescence pressure via ROS and inflammatory signaling (Figure2). Mitochondria are uniquely susceptible to lysine acetylation due to their alkaline matrix pH, high acetyl-CoA availability, and high c density of metabolic enzymes. In this environment, much of the protein acetylation occurs non-enzymatically, making the mitochondrial acetyl-proteome a powerful metabolic sensor of the organelle’s internal state. This spontaneous accumulation of acetyl groups is counterbalanced by NAD⁺-dependent deacetylase SIRT3, the dominant sirtuin in mitochondrial matrix (Baeza et al., 2016; Eftekhari et al., 2025). SIRT3 acts as a vital “deacetylation repair” system, removing inhibitory acetyl groups to preserve oxidative metabolism and mitochondrial quality control. For instance, caloric restriction boosts SIRT3 activity, which promotes the deacetylation and activation of SOD2 (superoxide dismutase 2), a primary antioxidant enzyme that neutralizes mitochondrial ROS. Elevated mitochondrial ROS serves as a leading upstream trigger of DNA damage signaling, NF-κB up-regulation, as well as pro-senescent SASP programs activation (Giralt & Villarroya, 2012; Qiu et al., 2010; Shimazu et al., 2025; Xu et al., 2024). Critically for metabolic disease, a high-fat diet leads to SIRT3 down-regulation and a subsequent surge in mitochondrial protein hyperacetylation. This pathological cascade accelerates obesity-associated phenotypes, such as steatohepatitis and insulin resistance, indicating that mitochondrial acetylation imbalance is a primary driver of disease progression rather than a mere correlation (Hirschey et al., 2011; Xian et al., 2025). This interpretation is also supported by a recent work linking age-related SIRT3 loss to the spread of pro-senescent signaling across metabolically active tissues (Šešelja et al., 2025).

Mechanistically, mitochondrial hyperacetylation leads to the organelle dysfunction, creating an increased “cargo burden” that upsurges the need for clearance via mitophagy. However, in the context of metabolic syndrome, a dangerous mismatch occurs; while mitochondrial damage increases the need for clearance, cytosolic autophagy is simultaneously constrained by the nutrient-activated mTORC1-p300 axis. This creates a state of ‘low clearance plus high damage’, which traps the cell into a cycle of chronic inflammation, defective quality control, and progressive senescent remodeling (Baeza et al., 2016; Hirschey et al., 2011). In this state sirtuins, especially SIRT3, serve as the central gatekeepers of mitochondrial quality control system (Lagunas-Rangel, 2025; Šešelja et al., 2025). Taken together, the mitochondrion exemplifies how organelle-specific acetylation dynamics establish a homeostatic “set-point”. Restoration of mitochondrial deacetylation capacity, specifically through SIRT3 activation or NAD⁺ supplementation, represents a mechanistically validated therapeutic strategy to restore cellular quality control and limit senescence-driven metabolic decline ( Figure 2) (Šešelja et al., 2025).

5. Tissue-Specific Manifestations of Metabolic Dysfunction

Having established the biochemical and molecular framework of the metabolic acetylation rheostat, we next examine how this regulatory system translates into tissue-specific pathologies. Although the acetylation-mediated regulation of autophagy and senescence represents a common cellular response to metabolic stress, its functional consequences differ across different organs according to their unique cellular composition, distinct metabolic functions, as well as their adaptive demands. In this section, we explore how this shared regulatory logic manifests in liver, adipose tissue, and other metabolically active organs; thereby linking a common upstream regulatory mechanism to diverse yet interconnected forms of metabolic dysfunction.

5.1. The Hepatic Acetylation Rheostat: Lipophagy vs. Fibrogenic Senescence

In the liver, acetylation-mediated regulation of autophagy and senescence is tightly coupled to the nutrient and stress signals through the EP300-SIRT1 axis, which serves as a molecular rheostat (Lee & Finkel, 2009; Mariño et al., 2014). Under nutrient-replete states, high levels of cytosolic acetyl-CoA stimulate EP300 activity, leading to the acetylation of various core ATG proteins (such as ATG5, ATG7, and ATG8/LC3), which suppresses autophagic flux. Conversely, during fasting states, the NAD⁺-dependent deacetylase SIRT1 removes these acetyl groups from the autophagic machinery and activates FOXO-regulated autophagy programs, effectively restoring cellular clearance (Lee et al., 2008; Lee & Finkel, 2009; Mariño et al., 2014). This acetylation rheostat is functionally critical for hepatic lipophagy, the selective autophagic degradation of lipid droplets. Specifically, ATGL-driven triglyceride mobilization requires the induction of SIRT1-dependent lipophagy for efficient lipid droplet catabolism and subsequent fatty-acid oxidation (Sathyanarayan et al., 2017). Consequently, a deacetylation deficit caused by impaired SIRT1 signaling weakens hepatic quality control by hindering both ATG protein function and FOXO-dependent autophagic programs (Cho et al., 2017).

In the context of chronic metabolic injury and steatohepatitis (MASH, formerly NASH), this same acetylation circuitry shifts to favor senescence. Senescent hepatocytes accumulate in steatotic livers, through the secretion of SASP-linked inflammatory and fibrogenic mediators, actively stimulate the transition of hepatic stellate cells into collagen-producing myofibroblasts. Furthermore, p300-regulated enhancer hyperacetylation reinforces these senescence-associated transcriptional programs, locking the liver into a state of chronic inflammation (Bonnet et al., 2022; Sen et al., 2019; Wijayasiri et al., 2022). Counter-regulatory SIRT1 signaling remains highly protective in this setting; for example, SIRT1 overactivation can reduce p53 acetylation within hepatic sinusoidal endothelial cells and hepatocytes, thereby blunting the p53/p21-dependent senescence and inflammatory signaling that drives liver fibrosis (Liu et al., 2024; Luo et al., 2021). Collectively, these findings support a model in which the hepatic acetylation state simultaneously dictates the balance between quality control and cell-fate remodeling. In this model, EP300-dominant states impair autophagic homeostasis and promote pro-senescent chromatin remodeling, while SIRT1-dominant states promote lipophagy and restrain the senescence-associated inflammatory milieu (Lee et al., 2008; Lee & Finkel, 2009; Mariño et al., 2014; Sen et al., 2019).

5.2. The Adipose Acetylation Rheostat: Autophagic Plasticity and Inflammatory Senescence

Expanding the tissue-specific landscape, the adipose tissue presents a highly compartmentalized acetylation profile that varies significantly across mature adipocytes, adipocyte progenitors, and stromal-vascular immune cells. Consequently, the same acetylation enzyme can produce cell-state-dependent outcomes that differ fundamentally from those observed in liver. In mature adipocytes, SIRT1 overactivation suppresses both autophagic flux and adipogenesis through a distinct tissue-specific mechanism. SIRT1 deacetylates and activates upstream signaling proteins, such as AKT and STAT3, which in turn engage the mTOR-ULK1 and p55 cascades to inhibit the autophagy pathway, ultimately restraining lipid storage (Tao et al., 2021).

However, the basal SIRT1 activity remains essential for adipose homeostasis. The loss of adipocyte-specific SIRT1 triggers obesity and insulin resistance characterized by defective autophagy and increased exosome release, mechanistically linking autophagic failure to endocrine and paracrine drivers of systemic insulin resistance (Li et al., 2019; Tao et al., 2021). During overnutrition, a reduction in SIRT1 levels leads to histone hyperacetylation, which facilitates ectopic pro-inflammatory transcription and macrophage recruitment. This establishes an inflammatory milieu that favors senescence-associated dysfunction. Collectively, these findings support a model in which the SIRT1 rheostat links autophagy and senescence in adipose tissue. While excessive SIRT1 activation may suppress necessary adipogenesis, and insufficient SIRT1 promotes inflammatory transcription, autophagic failure, and pro-senescent signaling (Gillum et al., 2011; Li et al., 2019; Tao et al., 2021).

In this context, autophagy serves as an intersecting remodeling pathway within the acetylation-senescence network: general autophagy is required for white adipocyte differentiation, while mitophagy is essential for the transition of beige adipocytes back to white adipocytes following thermogenic withdrawal (Altshuler-Keylin et al., 2016). A key metabolic marker in this process is PPARγ, whose acetylation increases as cells become senescent. This modification is oppositely regulated by p300 and SIRT1, as persistent PPARγ acetylation is considered pathogenic in aging and obesity. Conversely, SIRT1-regulated deacetylation of PPARγ at Lys268/Lys293 recruits PRDM16, pushing the transcriptional program towards a healthier, metabolically more protective brown or beige adipocyte (Han et al., 2010; He et al., 2023; Qiang et al., 2012). Concurrently, autophagy-driven mitochondrial turnover helps determine whether this thermogenic state is reversed or maintained. Finally, the acetylation of p53 directly tunes adipocyte senescence. For example, recent evidence indicates that the necdin-regulated blockade of the p53-p300 interaction reduces adipocyte p53 acetylation, senescence markers, as well as SASP in aged mouse models. This positions p300-depenent acetylation as a critical switch for adipose senescence during metabolic decline (Yang et al., 2025). Because p300 is also a primary regulator of autophagy suppression, it represents a definitive mechanistic point at which autophagy restraint and senescence signaling converge to drive adipose tissue dysfunction (Lee & Finkel, 2009; Yazıcı & McIntyre, 2025).

5.3. The Acetylation Rheostat in Other Metabolic Organs: Autophagy and Senescence in Inter-Organ Metabolic Regulation

Beyond the liver and adipose tissue, growing evidence indicates that the autophagy-senescence framework serves as a systemic regulator across diverse metabolically active organs, where acetylation-sensitive pathways dictate tissue adaptation or dysfunction.

Pancreas: In the pancreas, β-cell failure is driven by a combination of defective autophagy and persistent senescence triggered by glucolipotoxic stress, culminating in impaired insulin secretion and diabetes progression. However, SIRT1-dependent deacetylation is increasingly recognized as a critical upstream regulator that enhances β-cell fitness, stress resistance and anti-senescent adaptation, thereby linking acetylation status directly to insulin secretory capacity and survival (Hoseini et al., 2025; Jiao et al., 2025; Nguyen et al., 2024).

Intestine: In the intestine, autophagy conserves epithelial barrier integrity along with mucosal and microbial homeostasis, whereas intestinal aging often leads to epithelial dysfunction, inflammation, and senescence-associated barrier failure. Here again, acetylation is relevant; as recent work shows that SIRT1 helps preserve intestinal epithelial homeostasis by modulating stress and inflammatory signaling through acetylation-sensitive pathways. This suggests that the loss of intestinal deacetylation capacity may connect gut aging to systemic metabolic inflammation (Law et al., 2024; Raza, 2024).

Stomach: In the stomach, metabolic regulation is associated with gastric endocrine signaling rather than bulk tissue remodeling alone. Ghrelin-producing gastric cells influence nutrient sensing, appetite, systemic energy balance, and autophagy, and this axis is altered in obesity. Although direct evidence of senescence in stomach is less developed, but ghrelin is notably an acetylated hormone and its biology intersects with both autophagic pathways and aging-related metabolic decline. Further, its dependence on nutrient-responsive post-translational processing highlights a wider role for metabolic signaling modification in the gastric regulation of metabolic disease (Skoracka et al., 2025; Wu et al., 2024).

Hypothalamus: In the brain, specifically the hypothalamus, obesity-associated inflammation disrupts central energy circuits, whereas aging-associated neuroinflammation increasingly mimics senescence-like remodeling that worsens systemic metabolic control. In these settings, SIRT1 works as a central metabolic integrator, coordinating nutrient sensing, autophagy, and mitochondrial function while restraining inflammation. Consequently, reduced SIRT1 signaling in the brain is a major contributor to obesity-linked neural dysfunction and aging-associated metabolic decline (Le Thuc & García-Cáceres, 2024; Thapa et al., 2024; Yi et al., 2024).

Ultimately, these findings (as presented in Table 1) reveal that the acetylation-regulated autophagy-senescence axis is not limited to primary metabolic organs, but functions as a pervasive inter-organ system involving endocrine, neuroendocrine, and even central regulatory tissues.

6. Therapeutic Implications: Restoring Cellular Resilience

Having established that the acetylation-dependent dysregulation of autophagy and senescence occurs across multiple metabolic tissues, the next critical question is whether this pathological disruption can be therapeutically reversed. Since chronic metabolic stress drives the rheostat toward p300/CBP-mediated hyperacetylation and reduced sirtuin activity, restoring cellular resilience requires therapeutic strategies that relives both acetylation-regulated autophagic brakes and restrain senescence-linked inflammatory remodeling (Figure 3 and Table 1).

6.1. Targeting Acetyltransferase to Release Autophagic Brakes

Therapeutically, acetyltransferase, especially p300/CBP, represent highly appealing targets in metabolic disease because they sit at the intersection points of nutrient-associated transcription, and pro-senescent gene programs (Ghosh, 2021; Tabibzadeh, 2023). Targeting these acetyltransferases offers a direct mechanism to shift the cellular state towards enhanced autophagy and reduced senescence. Because p300/CBP functions as an endogenous repressor of autophagy, its pharmacological inhibition can effectively remove these brakes to restore cellular proteostasis and metabolic lipid handling (Y. Xu & W. Wan, 2023). For example, functional inhibitors such as spermidine, which inhibits EP300 activity, have been shown to promote autophagy across various animal models and cell types. This intervention is frequently categorized as a caloric-restriction-mimetic (CRM) route, providing the benefits of fasting, including dampened senescence-linked signalling, without the need for actual nutrient deprivation (Pietrocola et al., 2015).

In parallel, because p300 acts as a senescence amplifier by promoting the formation of de novo super-enhancers that sustain SASP expression, its inhibition serves as a powerful anti-senescence strategy. For example, A-485, a catalytic inhibitor of p300/CBP has shown significant metabolic benefits in preclinical models, including reduced hepatic gluconeogenesis and lipogenesis (Sen et al., 2019; Zhou et al., 2020). This illustrates how the targeted inhibition of acetyltransferases can reshape metabolic transcription to simultaneously favor autophagic promotion and the suppression of pro-senescent chromatin states (Table 1).

6.2. Enhancing Deacetylase Activity to Counteract Senescence

While inhibiting acetyltransferases removes the “brakes” on cellular quality control, targeting deacetylases, specifically NAD⁺-dependent sirtuins, provides a complementary route to actively restore autophagic flux and restrain senescence. SIRT1 emerges as a primary candidate in this strategy. It deacetylates core autophagy proteins (such as ATG5, ATG7, and ATG8/LC3) and related components to induce autophagy during nutrient or metabolic stress. This makes SIRT1 activation a logical therapeutic pathway for restoring the cellular autophagic clearance capacity that is typically lost in metabolic diseases (Lee et al., 2008).

In the context of senescence, SIRT1 functions as a critical negative regulator of p53-mediated growth arrest. By deacetylating p53 at Lys382, SIRT1 restrains its transcriptional activity, thereby helping to prevent or limit the transition into a stable, irreversible senescent state (Vaziri et al., 2001). Beyond SIRT1, SIRT6 exerts a powerful chromatin-based anti-senescence effect. SIRT6 specifically deacetylates H3K9 at NF-κB target promoters, effectively suppressing the NF-κB-driven inflammatory transcription that characterizes the SASP in metabolic tissues (Kawahara et al., 2009).

Evidence from disease models demonstrates that sirtuins-based strategies can simultaneously address both arms of the ‘double blow’. For example, resveratrol has been shown to alleviate hepatic steatosis by up-regulating SIRT1-deriven autophagic flux. This deacetylation-linked approach improves cellular clearance and reduces the chronic stress signals that would otherwise feed into the progression of cellular senescence (Table 1) (Ding et al., 2017).

6.3. Combined Rebalancing Strategies for Systemic Homeostasis

Given that aging and metabolic disease often create a dual imbalance, characterized by both excessive acetylation pressure and reduced deacetylation capacity, a combined strategy may be the more effective than aggressively targeting a single node hard. In this scenario, coupling KAT inhibition (such as functional EP300 inhibition with spermidine or catalytic p300/CBP inhibition with A-485) with sirtuin activation (via SIRT1/SIRT6-linked activators or NAD+ precursors) provides a synergistic mechanism to relieve the acetylation-imposed blockade on autophagy while repressing the epigenetic and transcriptional programs that lock cells into a senescent, pro-inflammatory SASP state (Kawahara et al., 2009; Lee & Finkel, 2009; Pietrocola et al., 2015; Sen et al., 2019; Vaziri et al., 2001). Ultimately, this rebalancing strategy targets the regulatory roots of metabolic decline rather than its downstream consequences, providing a robust framework for treating chronic disorders such as MASLD, obesity, and T2DM (Table 1).

6.4. Current Clinical Status and Drug-Development Landscape

From a translational perspective, the therapeutic strategies discussed above are advancing at different stages of development. Among them, KAT inhibitors, particularly those targeting CBP/p300, remain the least advanced for metabolic diseases. Although their mechanistic rationale is strong and several agents have entered early-phase oncology trials, their application in obesity, T2DM, and MASLD remains largely preclinical (Wu et al., 2025). In contrast, NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have already progressed into multiple human studies, including trials examining obesity-related phenotypes, mitochondrial function, insulin sensitivity, and broader metabolic outcomes. However, their clinical efficacy remains variable across tissues, patient populations, and dosing regimens (Chen et al., 2024; Vinten et al., 2025).

Sirtuin-based interventions occupy an intermediate position. For example, natural compounds, such as resveratrol have been evaluated in several human studies and remain attractive because of their favorable metabolic and anti-inflammatory profiles (Mansouri et al., 2025). Furthermore, selective synthetic activators, such as SRT2104 have reached phase I and early clinical studies, including investigations in healthy older adults and individuals with T2DM, but they have not yet matured into established metabolic therapies (Chang et al., 2024). Finally, spermidine is emerging as one of the most clinically tractable autophagy-enhancing natural compounds. Its progression into human interventional studies and an ongoing phase II trial highlights its promise as a CRM candidate (Thorup et al., 2025).

Taken together, the field is moving from mechanistic plausibility towards clinical translation, but various challenges remain, including the need to establish tissue-specific target engagement, develop reliable biomarkers of acetylation-state correction, ensure long term safety for chronic administration, and identify the patient populations most likely to benefit from rebalancing the acetylation rheostat.

7. Concluding Remarks and Future Directions

Overall, the evidence reviewed supports the protein acetylation as a fundamental, nutrient-responsive control layer that mechanistically couples acetyl-CoA/NAD⁺ homeostasis to the coordinated regulation of autophagic flux and cellular senescence in T2DM, obesity, and MASLD. In the context of aging and chronic overnutrition, this balance shifts toward persistent p300/CBP/EP300-driven acetylation with a concomitant decline in sirtuin-mediated deacetylation, creating a metabolic “double blow” to tissue homeostasis. On one hand, autophagic competence is progressively impaired at multiple levels, including core ATG protein function, ULK1/Beclin-1complex regulation, autophagosome maturation, and TFEB-driven lysosomal programs. On the other hand, senescence is simultaneously stabilized through chromatin and enhancer hyperacetylation together with the activation of non-histone effectors like p53, FOXO, and NF-κB, thereby reinforcing permanent growth arrest, SASP persistence, and chronic inflammatory remodeling.

Despite this strong mechanistic framework, clinical translation remains inadequate because of several unsettled bottlenecks. A major technical barrier is that acetyl-CoA and NAD⁺ are compartmentalized and highly dynamic metabolites, thus their real-time subcellular quantification within the living systems is intrinsically difficult (Brown et al., 2024; Eftekhari et al., 2025; Smith et al., 2025). Techniques such as mass spectrometry, although powerful, requires destructive sampling and thus cannot capture live metabolic flux, while current fluorescent biosensors still have limited resolution and provide incomplete spatial and temporal coverage (Smith et al., 2025). A related challenge is mechanistic attribution; since it remains technically difficult to distinguish enzymatic from non-enzymatic acetylation in vivo, particularly in mitochondria, it is often hard to determine which acetylation events are true drivers rather than secondary consequences of metabolic stress (Ali et al., 2018; Eftekhari et al., 2025).

Mechanistic translation is further complicated by target-related limitations. Because CBP/p300 are global transcriptional co-activators, and their direct inhibition may relieve autophagic suppression and dampen senescence programs, but it also carries the risk of broad off-target effects on essential gene networks, including developmental and tumor-suppression pathways (Gou & Zhang, 2024; Yazıcı & McIntyre, 2025). Similarly, SIRT1-regulated interventions remain limited due to the poor bioavailability, pleiotropic target engagement, and erratic clinical performance observed with compounds such as resveratrol (Brown et al., 2024; Salla et al., 2024).

Tissue specificity poses another translational obstacle. Although the acetylation-dependent regulation of autophagy and senescence clearly differs across liver, adipose tissue, intestine, pancreas, and brain; the approaches for organ-selective modulation remain underdeveloped. This raises the need for tissue-directed delivery systems, including prodrugs, nanoparticle or liposomal formulations, antibody conjugates, and other related targeted approaches capable of restoring the acetylation rheostat in diseased organs without upsetting parallel programs in other organs (Couvreur et al., 2023; Unagolla et al., 2024; Yang & Wang, 2024).

Furthermore, the causality problem is equally substantial. The majority of current evidence is derived from cell lines and animal models, whereas the direct causal link between altered acetylation, defective autophagic flux, and senescence stabilization in human tissues is still weakly established. This reflects not only the lack of some adequately specified perturbation tools, but also the fact that autophagic flux is a dynamic process rather than a static marker, and senescence, being a heterogenous state, cannot be captured by a single biomarker (Bahar et al., 2026; S. Li et al., 2025).

Thus, to overcome such limitations, future studies must prioritize integrated human-centered approaches, including biopsies, spatial multi-omics, inducible perturbation systems, and patient-derived organoid or iPSC platforms capable of resolving cell-type-specific metabolic and acetylation states. Equally important will be to define the functional outcomes of site-specific protein acetylation on shared autophagy-senescence nodes, such as ATG proteins, p53, PPARγ, NF-κB, FOXOs, and TFEB, while also developing standardized assays capable of robustly quantifying autophagic flux and senescence in human tissues. These advances will be instrumental not only for identifying the disease-driving acetylation events, but also for designing safer, tissue-informed rebalancing therapies. Whether through selective KAT inhibition (e.g., via A-485 or spermidine), enhancement of sirtuin-driven deacetylation (e.g., via SIRT1/SIRT6 activation) or rational combination approaches, the long-term objective of these strategies will be to restore the acetylation rheostat to its homeostatic set-point with sufficient mechanistic precision and clinical tolerability. Thus, if successfully translated, these strategies can lead to improved cellular quality control, limit senescence- and SASP-linked tissue damage, and ultimately slow metabolic decline and extend the health-span of patients with chronic metabolic disorders.