Metainflammation–Mitochondrial Dysfunction, and Organo-kine Crosstalk: A Central Axis Linking Metabolic Syndrome to Cardiovascular Diseases

1. Introduction

Metabolic Syndrome (MetS) is a global health concern that affects more than one in four adults worldwhide (Noubiap, J.J., Nansseu, J.R., Nyaga, U.F. et al. Worldwide trends in metabolic syndrome from 2000 to 2023: a systematic review and modelling analysis. Nat Commun 17, 573 (2026). https://doi.org/10.1038/s41467-025-67268-5). It is often associated with industrialized countries, where people are sedentary and constantly eat fast food that is characterized by being composed mainly of high levels of saturated fat, carbohydrates, sugar, and lipids, affecting the health and quality of life [1,2,3,4].

MetS is characterized by metainflammation, a result of genetic predisposition combined with changes in the body, such as obesity, insulin resistance, elevated abdominal circumference, dysglycemia, and cardiovascular disease (CVD) which also affect the liver, brain, and intestine [5]; [6]; [7]. These processes, when combined, affected the white adipose tissue (WAT). This endocrine tissue is responsible for the secretion of adipokines (such as leptin, visfatin, and resistin), cytokines, and cells, including endothelial cells, macrophages, fibroblasts, and leukocytes. When the WAT is continuously stimulated, adipocytes hypertrophy, increasing adipose tissue size. As a consequence, the secretory pattern of the tissue changes [8,9]. An example of this is the increase in leptin secretion, leading to hyperleptinemia, which can affect satiety. The lack of sensitivity to the hormone in the brain does not stop the hunger stimulus, even when people have already eaten enough [10]; [11].

Once the syndrome is established in the human body, there is an increase in pro-inflammatory adipokines produced by WAT, leading to chronic inflammation, increased secretion of pro-inflammatory cells, and decreased secretion of adiponectins. In this scenario, there is also an elevated production of reactive oxygen species (ROS), due to mitochondrial dysfunction, resulting in oxidative stress that can lead to irreversible systemic tissue damage [12]; [13]. The mitochondria are cellular organelles responsible for producing energy by generating adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). In normal conditions, this organelle produces ROS, but enzymes neutralize them before they can damage mitochondria and other organelles. However, due to insulin resistance, the organism in the MetS works differently, altering normal metabolic functions, causing mitochondrial dysfunction and, consequently, altering the electron transport chain, producing ROS that are no longer fully neutralized. In addition to this factor, mitochondrial dysfunction results in ATP deficiency, disrupting all cellular processes that require energy, and can lead to apoptosis [14,15]. Figure 1 summarizes the central axis of MetS: metainflammation, oxidative stress, and mitochondrial dysfunction.

The consequences of these changes in the body can lead to lower cognitive performance, vascular dementia, tissue fibrosis, atherogenesis, and other cardiovascular problems (Mutruc et al., 2025; Zouridis, Nasir, Aspichueta, & Syn, 2024, 2025). For example, studies have shown that oxidative stress is linked to atrial fibrillation and can also contribute to neuroinflammation. Others have demonstrated a relationship between hepatic and pancreatic steatosis [16]; [17]. Regardless of location, mitochondrial dysfunction and oxidative stress induced by MetS result in systemic changes, altering the function of several organs and causing various diseases [18]; [19]; [20]; [21].

Although metainflammation, oxidative stress, mitochondrial dysfunction, organokine imbalance, and gut microbiota dysbiosis have each been implicated in MetS, these processes are often discussed as separate mechanisms. This fragmented view limits understanding of how local metabolic stress in adipose tissue, skeletal muscle, liver, heart, bone, kidney, and intestine becomes translated into systemic cardiometabolic injury. In particular, the integration of mitochondrial dysfunction with organokine-mediated interorgan crosstalk remains insufficiently synthesized, despite its potential relevance for biomarker discovery and multi-target therapeutic strategies.

Therefore, this review aims to synthesize current evidence on the metainflammation–mitochondrial dysfunction axis in MetS, with particular emphasis on organokine-mediated interorgan crosstalk, gut microbiota-derived metabolites, and their contribution to cardiovascular disease progression. By integrating these mechanisms, this review seeks to provide a systems-level framework for identifying convergent biomarkers and therapeutic targets in cardiometabolic disease.

2. Metabolic Syndrome and Metainflammation

MetS, also known as Syndrome X and VIRAS (visceral insulin resistance adiposity syndrome), is associated with obesity (primarily abdominal fat), insulin resistance, hypertension, elevated triglycerides, and reduced high-density lipoprotein (HDL-c) [22]; [23]. This scenario is more prevalent in adults, it is closely related to the risk for CVD, and it is a warning sign, since CVD are the leading cause of death in the world [1]. Studies have shown that obese individuals experience a significant increase in white adipose tissue throughout the body [24]. This change alters the integrity and sensitivity of cells to hormones such as insulin and adiponectin, contributing to metabolic dysfunction [25]; [26]. Besides WAT, there is also the brown adipose tissue (BAT) which plays distinct functions. The first type is characterized by cells containing a large unilocular lipid droplet that is associated with metabolism and fat storage and also serves an endocrine function [3]. These cells can be found in the viscera or subcutaneous tissue [27]. At the same time, the second is associated with the body's thermal regulation, because its cells have a high mitochondrial density, enabling energy dissipation through uncoupled mitochondrial respiration that produces heat and maintains body temperature [28]; [29]; [30]. In patients with MetS, the excess calorie consumption leads to an increase in the amount of visceral WAT. As a result, the white adipose tissue will be responsible for the release of hormones and pro-inflammatory cells that will cause imbalance in glucose metabolism, insulin resistance, liver complications, and increased release of free fatty acids (FFA) and cholesterol, establishing a condition known as metainflammation [31]; [32]; [33]; [34].

Once installed, this syndrome causes a series of changes in human metabolism. Adipose tissue is the most active due to the shift in the secretory pattern, releasing pro-inflammatory mediators, such as macrophages, tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), IkB kinase (IKK), and Jun N-terminal kinase (JNK) in adipocytes, which are the main changes caused by metainflammation [35]; [36]; [37]; [38]. Macrophages (classified as M1 in this case) derived from monocytes leaves the bloodstream and are responsible for triggering a series of inflammatory responses in adipose tissue. They release excess free FFA through changes in lipolysis which can activate JNK and IKKα. The IkB kinase mediators (IKKα and JNK), when activated, are responsible for the cascade release of pro-inflammatory mediators, in addition to causing insulin resistance [39]. Furthermore, interleukin-6 (IL-6) that is released by adipocytes and macrophages has been associated with endothelial dysfunction. After release, it stimulates the renin-angiotensin system to express more angiotensin II type 1 receptors (AT1) which are related to the development of atherosclerosis [40]; [41]; [42]; [43]; Furthermore, TNF-α release contributes to adipocyte hypertrophy and stimulates hepatic lipolysis leading to increased circulating FFA [44]; [45];[46]; [47]. With all these changes, several vicious cycles are established; for example, insulin resistance is linked to the development of obesity, and obesity also leads to insulin resistance [48]; [49]; [50].

Normally, the binding of insulin to the receptor (IRS) leads to the phosphorylation of tyrosine kinase residues in the beta subunit, triggering a signaling cascade within the cell that culminates in the release of GLUT-4 (an insulin-sensitive glucose transporter) to the cell's plasma membrane. However, in metainflammation, IkB kinases (IKKα and IKKβ) are activated and phosphorylate serine/threonine residues in IRS proteins, thereby preventing the signal transduction cascade initiated upon insulin binding to its receptor and causing insulin resistance [51]. Furthermore, in addition to the mentioned cells, adipocytes, when hypertrophied in cases, such as metainflammation, not only influence the circulating levels and metabolism of cholesterol but also drive an exaggerated inflammatory response. This inflammatory response leads to an excessive increase in the release of pro-inflammatory adipokines [52]; [53]; [54]. In obese individuals, there is a greater release of leptin (leading to leptin resistance), TNF-α, IL-6, and monocyte chemoattractant protein-1 (MCP-1), and a lower release of adiponectin and omentin. This results in a greater presence of pro-inflammatory adipokines and a lower presence of anti-inflammatory adipokines exacerbating metainflammation [55]; [56]. Thus, mediators such as leptin acts on the hypothalamus to reduce hunger and are elevated in overweight individuals. However, due to the organism's inflammatory state, this adipokine cannot efficiently perform its role, characterizing leptin resistance in individuals with MetS [57]; [58]. In contrast, adiponectin which facilitates greater glucose entry into cells by increasing insulin sensitivity is present in lower percentages in metainflammation. This factor further contributes to the development of type 2 diabetes mellitus (T2DM) in individuals with MetS [59].

These chronic inflammation processes alter communication between tissues, such as the intestine-liver-adipose axes. In addition to all the relationships between adipocytes and hepatocytes mentioned above, there is also a decrease in adipocyte energy expenditure, since the action of fibroblast growth factor-21 (FGF21), an endocrine hormone released by hepatocytes, is reduced in adipose tissue [60]; [61]; [62]. The mechanism of action of FGF21 involves binding to its receptor (FGFR1c), as well as its coreceptor, β-klotho, which is expressed only in metabolic tissues [63]. Studies indicate that, once bound to its receptor, FGF21 increases glucose uptake in WAT, thereby improving adipocyte thermogenesis and contributing to reduced insulin resistance and increased adiponectin secretion [64]; [65]. The reduction in its action during obesity, even with high liver production of this hormone, is due to receptor resistance to FGF21, which is caused by the individual's inflammatory state. Consequently, changes in adipose cell metabolism lead to increased fat storage and, as a domino effect, resulting in weight gain [66]; [67].

All of these changes cause an imbalance in metabolism, leading to the release of mediators that, rather than reducing the inflammatory state, further increase it, impairing the organism's overall functioning and creating a vicious cycle of inflammation and oxidative stress [68]; [69]; [70].

3. Oxidative Stress as an Amplifier of Metainflammation and Vascular Injury in MetS

As previously shown, in MetS, the sustained intake of calories contributes to the inflammatory process in WAT, leading to alterations in lipid metabolism. A series of studies has shown that, at the molecular level, mitochondria in WAT produce ROS, leading to mitochondrial dysfunction and lipid oxidation [23,71,72,73]. The mechanism is composed of a series of altered reactions due to a large amount of electrons being transferred to the respiratory chain (during energy production by mitochondria), resulting in an imbalance between antioxidant and oxidant species. The most serious consequence of this imbalance is that reactive oxygen species can interact with the cell's DNA, altering protein function or disrupting signaling pathways, ultimately leading to programmed cell death [74,75,76].

In the inner mitochondrial membrane, during the mitochondrial electron transport chain (ETC), the NADH (nicotinamide adenine dinucleotide) molecule donates an electron to ubiquinone (CoQ), generating the reduced molecule ubiquinol (QH2) [77]. QH2 is oxidized by complex III, removing electrons from the molecule one at a time, which are transferred to cytochrome C. Then, this cytochrome carries these electrons to complex IV, and oxygen serves as the final electron acceptor, generating water. All these oxidation and reduction reactions create an electrochemical gradient across the membrane spaces. Ultimately, during the entry of H+ into the mitochondrial matrix, ADP is phosphorylated to ATP [78]. In metabolism, reactive oxygen species are produced in the mitochondria during the reduction of NADH to NAD+ in oxidative phosphorylation [79]. The NADPH (nicotine adenine dinucleotide phosphate) oxidase family of enzymes is extremely important in understanding the mechanism of oxidative stress, since the enzyme NADPH oxidase 2 (NOX2) (catalytic subunit of NADPH) is responsible for the overproduction of ROS [80]; [81]; [82].

When an individual consumes high-calorie foods or expends more energy than they can metabolize during the day, nutrients accumulate in the body. This excess of ingested nutrients causes an overload of oxidative phosphorylation [83]. This excess of ingested inputs for metabolism leads to an overload of oxidative phosphorylation [84]. Associated with this overload, individuals with MetS are constantly under metabolic stress, as a significant amount of NADH is released, and the body requires little ATP [85]. Since the caloric expenditure is small compared to the food intake, there is a disproportion between the amounts of NAPH and NAD+ [86,87,88]. All of this, when combined, generates an escape of electrons during their transfer between the complexes, reacting with oxygen and forming $0_2$^-. Together, these changes promote electron leakage from the mitochondrial respiratory chain, allowing partially reduced oxygen species, particularly superoxide anion, to accumulate and initiate downstream oxidative damage [75,89,90].

Once produced, ROS directly promote an inflammatory environment, as they activate NF-κB (nuclear factor-κB) transcription, a complex involved in the immune response during inflammation [91]; [92]; [93]. This factor is responsible for activating signaling pathways that produce pro-inflammatory cytokines, including IL-6, TNF-α, and MCP-1, as well as IL-1β. These cytokines, in turn, attract additional pro-inflammatory cells, leading to angiogenesis and fibrosis. Furthermore, they can act on the cell nucleus, resulting in cellular dysfunction[94]; [95]. In addition, TNF-α inhibits insulin receptor signaling in cells, leading to increased insulin resistance and, in turn, enhanced lipolysis, the release of free fatty acids into the circulation, and decreased glycogen synthesis [96,97,98]. All these processes are closely linked to the establishment of an environment characterized by chronic inflammation and oxidative stress, which, consequently, leads to MetS. The consequence is that normal metabolic reactions are affected and adipose tissue function is altered, leading to changes in systemic metabolism [99]; [95]. One of the major problems with this syndrome is that, once established, the release of pro-inflammatory factors attracts additional inflammatory cytokines, forming a vicious cycle [100]; [101].

High levels of ROS cause vascular endothelial dysfunction, as these molecules induce lipid peroxidation and protein oxidation and can even lead to changes in cellular DNA [102]; [103]. In addition, ROS can alter the expression of adhesion molecules, such as P- and E-selectins, on endothelial cells, leading to endothelial dysfunction [104]; [105]. These cellular changes induced by ROS damage the cell membrane, releasing DAMPs (damage-associated molecular patterns) and PAMPs (pathogen-associated molecular patterns), which activate inflammatory pathways [106]. As noted above, cells such as macrophages and neutrophils are recruited to the tissue, where they attempt to eliminate the aggressive agent by releasing cytokines such as TNF-α and IL-6, which, in turn, attract additional inflammatory cells, creating a constant inflammatory environment [107]; [108]. Still in the vascular bed, the homeostatic imbalance of ROS leads to the oxidation of low-density lipoprotein (LDL-c). Macrophages recognize the oxidized LDL (ox-LDL) through scavenger receptors as a foreign cell, and the macrophages phagocytose the ox-LDL, generating foam cells [109]; [110]. After that, with a dysfunctional endothelium, these foam cells adhere to the intimal layer of the vessel, initiating atherosclerotic plaque formation [111]; [112]; [113]. Over time, ROS excess causes the rupture of endothelial cell junctions. It increases vascular permeability, allowing foam cells to accumulate in the vessel and form an atherosclerotic plaque, which narrows the blood vessel lumen and hinders blood flow. If this occurs in the coronary artery, the obstruction of the vessel leads to infarction [114]; [115]; [116]; [117]. In another scenario, oxLDL-like receptor selectin (LOX-1) recognizes the foam cells. It activates platelet aggregation, initiating an interaction between platelets and the endothelium that, together with the action of ROS on the release of MMPs (matrix metalloproteinases), is responsible for breaking down the fibrotic layer of the atheroma plaque, leading to the formation of a thrombus [118]; [119]; [120]. Once formed, this thrombus can travel through the blood vessels, reaching the heart, where it can obstruct the coronary arteries and cause a heart attack [121]; [122].

4. Mitochondrial Dysfunction as a Bioenergetic Driver of MetS Progression

As pointed out above, mitochondria are cellular organelles present in the cytoplasm of eukaryotic cells and are composed of two membranes, one internal and one external [123]; [124]. In their normal functioning, the primary function of these organelles is to generate energy, that is, to produce ATP through compounds such as sugars, amino acids, and fatty acids [125]; [126]. When these nutrients are transported into the mitochondrial membrane they undergo oxidation through the tricarboxylic acid cycle and beta oxidation [127]. During the degradation of these compounds, electrons are released and captured by the molecules NAD and FAD (nicotinamide and flavin adenine dinucleotide), which are then reduced to NADH and FADH₂ [128]; [129]. After that, these molecules donate their electrons to the electron transport chain, which, in turn, generates ATP through ATP synthase after a series of events, thereby completing the process known as oxidative phosphorylation [130]. In MetS, the main mitochondrial alterations are ROS generation, membrane and mitochondrial DNA (mtDNA) damage, and decreased ATP production [131]; [132];[133]. Beyond classical bioenergetic pathways, tryptophan–kynurenine metabolism may also connect inflammatory signaling to mitochondrial ATP maintenance, redox regulation, NAD⁺ metabolism, mitophagy, and inflammasome control [134,135]. Figure 2 shows an overview of mitochondrial alterations observed in metabolic syndrome.

In individuals with this syndrome, adipocyte hypertrophy causes an overload during energy-generating processes in the organelle, especially during oxidative phosphorylation. This disruption of mitochondrial homeostasis results in electron leakage during NADH- and FADH₂-mediated electron transfer, generating ROS. These reactive species remain unneutralized due to overloaded antioxidant defenses, ultimately leading to mitochondrial dysfunction [136,137]. In skeletal muscle, mitochondrial dysfunction induced by oxidative stress reduces lipid utilization as an energy source [138]. The normal and functional state of beta-oxidation is disturbed by ROS generation and, as a result, non-oxidized free fatty acids, such as diacylglycerides and ceramides, accumulate in other tissues, modulating tissue cell signaling and generating insulin resistance [130]; [139]; [140]; [141]. In addition, AMP-activated kinase (AMPK) plays a crucial role in the generation of ATP within mitochondria [142]; [143]. This enzyme is activated when the available energy in the cell drops, that is, when ATP levels are low, and its primary function is to interrupt anabolic pathways and activate catabolic pathways [144]; [145]. In dysfunctional mitochondria, there is decreased AMPK synthesis, leading to increased lipogenesis and reduced FFA oxidation, factors that further increase insulin resistance in individuals with MetS [146]; [147]; [148].

A decrease in mtDNA is important for carrying out functions such as the production of constituents necessary for mitochondrial function, which is also associated with MetS [149]; [150]. Several copies of mtDNA are present within the mitochondrial matrix. Its alteration is susceptible in individuals with the syndrome because it is located near the electron transport chain and is susceptible to changes during oxidative stress [151]; [152]; [153]; [154]. The primary consequence of this alteration in mtDNA is a decrease in its copies, leading to deficiencies in OXPHOS proteins (oxidative phosphorylation) and activating the transcription factor-1 [106]; [155]; [156]. This factor is responsible for activating the polarization of M1 macrophages. Then, they will release a series of pro-inflammatory mediators, which, as a final result, lead to an increase in insulin resistance [157]; [158]; [159]. In addition to these changes, studies show that MetS is associated with decreased mitochondrial DNA copy number (mtDNA NC) and this change in mtDNA copy number is associated with an increased risk of type 2 diabetes [160]; [161]. Moreover, studies have proven a relationship between the formation of atheroma plaques and a decrease in mtDNA [162]; [163]; [164].

During mitochondrial dysfunction, processes such as mitophagy (elimination of damaged mitochondria) are deregulated, leading to the activation of inflammasomes and further increasing the inflammatory state, which, as previously demonstrated, contributes to the formation of atheroma plaques [165]; [166]; [167]; [168]. Furthermore, mtDNA is closely linked to cell death[169]. mtDNA is released into the cytosol under conditions of mitochondrial stress via signaling from the pro-inflammatory cytokines TNF-α and IL-β [153]; [170]; [171]. The mechanism by which this occurs is that, once mtDNA is recognized outside the mitochondrial matrix as a DAMP, it triggers a series of intracellular signaling processes that ultimately aim to induce apoptosis [172].

From a systemic perspective, renal cells with accelerated metabolism, which constantly require ATP, are also susceptible to mitochondrial dysfunction. Studies show that mitochondrial ROS production in tubular cells damages these cells, which are sensitive to toxicity, and alters mitochondrial energy production, resulting in cell death [173]; [174]. This factor, combined with the changes already mentioned in liver and heart tissues, suggests that MetS does not occur solely in adipose tissue, necessitating careful examination of the organs affected [175]; [176]; [177].

5. Gut Microbiota-Derived Metabolites as Modulators of Metainflammation and Mitochondrial Dysfunction

In general, humans and the intestinal microbiota form a symbiotic relationship of commensalism, orchestrated by positive or negative feedback mechanisms [178]; [179]; [180]. The microbiome is an intestinal system of microbial mass, which means it is composed of bacteria and their metabolic activities [181] [182]; [183]. The importance of this system lies mainly in its ability to digest non-digestible substrates, such as dietary fiber [184]. Through the fermentation of these carbohydrates, these microorganisms produce short-chain fatty acids (SCFAs). Among these are butyrate, acetate, and propionate, which are part of a group that has 1 to 6 saturated carbons in its composition [185]; [186]. Through mechanisms that regulate energy expenditure, these SCFAs balance glucose metabolism, influence appetite, modulate the immune system, and directly impact metabolic health [187]; [188]. Among their primary functions, these SCFAs provide energy to colonocytes, ensuring the system's sustainability. Additionally, they can be absorbed and enter the peripheral circulation via the portal system, thereby ensuring systemic effects [189]. The high production of these metabolites may be related to the prevention of gastrointestinal dysfunctions and other metabolic disorders, such as obesity. Conversely, the opposite is also observed [190]. Still in the gastrointestinal tract, SCFAs have affinity for G-protein coupled receptors (GPCRs) related to the regulation of satiety and intestinal motility, since they stimulate the secretion of glucagon-like peptide-1 (GLP-1) and intestinal hormone peptide YY (PYY) through the L cells of the intestine [191]; [192]. Furthermore, when activated, these receptors promote the activation of immune system cells, leading to the release of prostaglandin E2 and IL-10 which together mediate an anti-inflammatory action and regulate intestinal cell proliferation [193].

In the case of MetS, several authors have reported an association between decreased SCFA-producing bacteria and increased pathological mechanisms of the disease [194]; [195]. By binding to GPCRs (e.g., GPR43), these metabolites activate pathways that stimulate GLP-1 secretion. As a multifunctional incretin hormone, GLP-1 enhances insulin sensitivity and promotes its secretion from pancreatic β-cells, directly countering insulin resistance, a key determinant of MetS [196]; [197]; [198]; [199]. In addition, its action on pancreatic beta cells promotes insulin secretion, which also helps regulate serum glucose levels [200]. Evidence for this lies in the high incidence of MetS risk factors in Western populations where dietary patterns are characterized by low fiber intake [201]. Critically, GPR43 activation inhibits insulin-mediated lipid and glucose deposition in adipose tissue. Consequently, a deficiency in SCFAs, which stimulates GPR43, promotes ectopic fat accumulation while reducing muscle utilization of these substrates. This process directly contributes to abdominal obesity, a core determinant of MetS [202]; [14]; [203]. Thus, it is evident that the intestinal microbiota and its mechanisms of self-regulation and metabolic regulation influence systemic factors that determine predisposition, the presence of risk factors, and even the severity of MetS.This is why the microbiome is also strongly associated with possible treatments for MetS, seeking to maintain this system as a path to metabolic balance [204]; [205]; [206]; [207] J. Figure 3 summarizes the role of gut microbiota, SCFAs, and Metabolic syndrome.

Several studies have found that supplementation with probiotics will increase the amount of intestinal bacteria that produce SCFAs and it is a solution for reducing risk factors for the syndrome. The administration of Bifidobacterium lactis was associated with a reduction in hepatic gluconeogenesis and improved translocation of the glucose transporter-4 (GLUT4), reducing insulin resistance [193]; [208]; [209]; [210]. In addition, the increase in fiber intake creates an environment conducive to the proliferation of these bacteria, thereby positively influencing the stabilization of the fermentation process and the production of SCFAs. Thus, increased fiber intake is positively associated with reduced body adiposity which directly influences MetS [211]; [212]. For these reasons, studies indicate that factors associated with greater GLP-1 release, such as the high production of SCFAs by the intestinal microbiota through fiber intake, are directly related to MetS [213]. Furthermore, studies indicate that factors associated with greater GLP-1 release, such as the high production of SCFAs by the intestinal microbiota through fiber intake, are directly associated with attenuation of MetS and a reduction in its risk factors for future cardiovascular and metabolic diseases. Collectively, these findings suggest that dietary fiber, SCFA-producing bacteria, and GLP-1-mediated signaling form a microbiota–metabolic axis that may attenuate insulin resistance, adiposity, and cardiovascular risk in MetS [74,214,215,216].

6. Organokine-Mediated Interorgan Crosstalk in Metabolic Syndrome

Different organokines play a specific role in MetS. Table 1 summarizes their general functions and the effects related to MetS.

In individuals with MetS, chronic low-grade inflammation, driven by sustained positive energy balance (high caloric intake and reduced expenditure), alters the secretion profiles of hepatokines, myokines, adipokines, and cardiokines [217]. Dysregulation of the release of these proteins strongly influences the development and progression of MetS and, consequently, cardiovascular diseases [218]; [219]; [217]; [220]; [221] (Figure 4).

6.1. Adipokines: Adipose Tissue Inflammation and Insulin Resistance

Since its discovery, studies on adiponectin, leptin, adipsin, and other adipose tissue secretions have advanced, particularly regarding the organ’s importance in regulating metabolism. Adipokines are protein hormones released by adipocytes in response to the body’s metabolic conditions. In general, they perform their functions by regulating glucose and lipid metabolism, modulating immune responses, and regulating the body’s response to insulin [222]; [223]; [224]. Due to their fundamental role in metabolic homeostasis, several pharmacological and therapeutic interventions targeting adipose tissue are being developed for the treatment of obesity, type 2 diabetes, cardiovascular disease, and MetS.

Leptin is a crucial ally in weight loss, as it suppresses hunger, increases energy expenditure, and influences the immune system. In obese individuals, as noted above, the body may exhibit leptin resistance ([225]; [226]). High circulating levels of resistin are associated with metabolic disorders, indicating the presence of inflammation and insulin resistance [227];[228]. Adiponectin has beneficial effects on the body by promoting insulin sensitivity, inhibiting the formation of atherosclerotic plaques, and exerting anti-inflammatory effects. However, its levels are low in people with obesity and MetS [229]; [230].

6.2. Hepatokines: Liver-Derived Regulators of Lipid and Glucose Homeostasis

In liver tissue, hepatokines influence metabolism and are associated with the pathogenesis of MetS. In general, these molecules are capable of controlling lipid and glucose metabolism, maintaining whole-body homeostasis, increasing insulin resistance, and acting as pro-inflammatory factors [231]; [232]. These functions highlight the liver’s crucial role in the development of metabolic disorders associated with overnutrition. In MetS, hepatokines are linked to increased oxidative stress, endoplasmic reticulum stress, altered insulin signaling, altered lipid profiles, mitochondrial dysfunction, and lipid accumulation in the liver and skeletal muscle [233]; [234]; [235]; [236].

In addition to being secreted by various tissues such as the liver, pancreas, muscle, and adipose tissue, Fibroblast growth factor-21 (FGF-21) plays essential roles in metabolism. FGF-21 increases glucose uptake by adipose tissue, exhibits anti-inflammatory effects, and also participates in adipose tissue browning [237]; [238].

Growth differentiation factor 15 (GDF-15) is associated with appetite regulation and increased insulin sensitivity, and contributes to weight loss by increasing energy expenditure [239]; [240].

Fetuin-A is widely used as a marker for metabolic diseases, especially type 2 diabetes mellitus (T2DM), as its action is associated with increased insulin resistance [241]; [242].

Angiopoietin-like 4 (ANGPTL4) has been associated with stimulating lipolysis and is also responsible for fat redistribution ([204]; [243]).

6.3. Myokines: Skeletal Muscle Metabolism and Exercise-Responsive Signaling

Skeletal muscle has essential functions in the body, in addition to producing mechanical energy and influencing basal metabolism, it also exhibits secretory activity, releasing myokines [219,220,221]. These molecules are bioactive peptides released by muscles and exert their functions through autocrine, paracrine, and endocrine effects. Its main functions include increasing insulin sensitivity, regulating lipolysis, inflammation, and metabolic homeostasis. These factors highlight physical exercise and increased muscle mass as important allies in the treatment and prevention of MetS [222,223,224]. For example, irisin is responsible for the browning of brown adipose tissue and also exhibits anti-inflammatory properties [225]; [226]. IL-6 released after physical exercise has been shown to affect lipid metabolism by increasing lipolysis, and it is also associated with increased glucose uptake in muscle. Myonectin has effects on the oxidation of free fatty acids and also increases glucose uptake by skeletal muscle [227,228].

6.4. Cardiokines: Cardiac Stress Signals and Cardiometabolic Remodeling

Similar to liver and adipose tissue, skeletal muscle and cardiac tissue also have endocrine actions. Cardiokines, proteins secreted by cardiomyocytes, have beneficial effects on regulating metabolism, such as stimulating lipolysis, and play a crucial role in systemic anti-inflammatory responses. Cardiokines influence cardiac stress, reduced muscle mass, atherosclerosis, diabetic cardiomyopathy, and heart failure ([244]; [245]; [246]; [247]. For example, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are the main cardiokines released by the heart. These hormones are cardioprotective and have recently been identified at reduced levels in obese individuals. They affect lipid and free fatty acid metabolism and are linked to improved insulin sensitivity [248]; [249].

Myostatin, found in high levels in individuals with MetS, has the ability to alter mitochondrial function, thereby affecting lipid metabolism, increasing insulin resistance, and decreasing muscle mass [250]. Myonectin is responsible for increasing the uptake of free fatty acids by adipose and hepatic tissue and may be associated with insulin resistance when circulating at low levels [251]; [252]. Therefore, new treatments targeting the adipomyocardiokine axis may help treat cardiovascular disease, obesity, and metabolic syndrome (MetS), as these tissues communicate and influence one another.

6.5. Osteokines and Renokines: Bone–Kidney Contributions to Systemic Metabolic Dysfunction

In the bones, osteokines exert a significant influence on MetS through multiple mechanisms (“Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report,” 2002). Their actions involve regulating insulin sensitivity and glycemic homeostasis. Examples include osteocalcin, which stimulates pancreatic beta-cell proliferation and insulin secretion [253]. Furthermore, it promotes increased glucose uptake in muscle and adipose tissue via activation of the AMPK/FOXO1 pathway. It reduces pro-inflammatory cytokines, such as TNF-α and IL-6, and oxidative stress. It reduces lipid accumulation and activates antioxidant pathways, such as the Nrf2 pathway. It also aggravates hepatic and systemic inflammation [254]; [255].

Sclerostin inhibits the Wnt/β-catenin pathway, impairing insulin signaling and contributing to insulin resistance [256] FGF-23, when elevated, is associated with hepatic steatosis; it induces vascular calcification and endothelial dysfunction, increasing the risk of hypertension and cardiovascular events [14]. Neutrophil gelatinase-associated lipocalin (NGAL), also known as lipocalin-2, improves glucose intolerance via PPARγ, and in excess, it exacerbates inflammation. It also modulates hepatic adipogenesis, influencing abdominal circumference [257]. Therefore, an imbalance in osteokines promotes insulin resistance, dyslipidemia, chronic inflammation, and hepatic steatosis, amplifying the components of metabolic syndrome.

As previously mentioned, individuals with MetS experience systemic changes, including kidney involvement. When released, renokines primarily affect glucose and lipid metabolism, but they also influence blood pressure through the renin-angiotensin-aldosterone system (RAAS) [258]; [259]. For example, erythropoietin, in addition to its role in erythrocyte production, has been associated with improved insulin sensitivity and vascular endothelial protection and may even aid in weight loss [260]; [261]; Renin, through the RAAS, has been strongly associated with hypertension in patients with MetS; it also has effects on oxidative stress and insulin resistance [262]; [263]. NGAL is known to be a marker of cell injury, and elevated levels of this biomarker are present in people with diabetic nephropathy [264]. Furthermore, NGAL participates in immune responses, and although its involvement in glucose homeostasis and lipogenesis in individuals with MetS is not yet fully understood, this molecule may play a role in these processes [265]; [266].

In summary, these biomarkers are essential for the establishment and progression of MetS, since, in general, when released, myokines, hepatokines, adipokines, cardiokines, osteokines and renokines are responsible for increased insulin resistance, modulation of adipose tissue with increased lipolysis, changes in glucose metabolism, increased pro-inflammatory cytokines, hypertension, and heart, liver or kidney disease

6.6. Integrated Organokine Crosstalk in MetS

In a scenario of systemic inflammation and insulin resistance, all organokines (In a scenario of systemic inflammation and insulin resistance, all organokines (hepatokines, myokines, cardiokines, adipokines, osteokines, and rinokines) are involved in the regulation of inflammation, lipid and glucose metabolism, and insulin sensitivity. MetS is related to an imbalance in these molecules that promote insulin resistance (thanks to the inhibition of signaling pathways, such as Wnt/β-catenin and AMPK), mitochondrial dysfunction, and oxidative stress; accumulation of lipids in tissues such as liver, muscle, and heart; and hypertension and cardiovascular diseases [323]; [324].

In the muscle-liver-adipose tissue axis, it is possible to mention that myokines (such as irisin and myostatin) and hepatokines (such as FGF-21) can modulate the browning of adipose tissue, increasing energy expenditure and reducing adiposity. Adipokines (such as leptin and adiponectin) regulate fatty acid oxidation in muscle and liver. FGF-21 (secreted by liver, muscle, and adipose tissue) acts as a central metabolic regulator, improving insulin sensitivity and lipid homeostasis [24,25].

As seen above, some molecules can be secreted by multiple tissues and have integrated roles that are summarized in Table 2 and Figure 5.

Figure 5. Illustration of interorgan communication mediated by organokines—bioactive molecules secreted by various organs involved in metabolic regulation. Skeletal muscle (myokines), liver (hepatokines), adipose tissue (adipokines), heart (cardiokines), bone (osteokines), kidney (renokines), and intestine (enterokines) release signaling molecules such as irisin, FGF-21, adiponectin, PNA, osteocalcin, erythropoietin, and GLP-1. These organokines modulate inflammation, insulin sensitivity, lipid metabolism, and vascular function. Dysregulation of this interaction plays a crucial role in the pathogenesis of MetS and its cardiometabolic complications. Abbreviations:.

Figure 5. Illustration of interorgan communication mediated by organokines—bioactive molecules secreted by various organs involved in metabolic regulation. Skeletal muscle (myokines), liver (hepatokines), adipose tissue (adipokines), heart (cardiokines), bone (osteokines), kidney (renokines), and intestine (enterokines) release signaling molecules such as irisin, FGF-21, adiponectin, PNA, osteocalcin, erythropoietin, and GLP-1. These organokines modulate inflammation, insulin sensitivity, lipid metabolism, and vascular function. Dysregulation of this interaction plays a crucial role in the pathogenesis of MetS and its cardiometabolic complications. Abbreviations:.

Figure 6. Schematic representation of the interaction between MetS and organ-specific cytokine signaling. MetS, characterized by metainflammation, insulin resistance, visceral obesity, dyslipidemia, and hypertension, modulates and is modulated by the dysregulated secretion of different organokines. These include altered levels of cardiokines (e.g., decreased ANP, increased BNP, and GDF-15), adipokines (such as increased leptin, visfatin, and resistin; decreased adiponectin and omentin), myokines (such as decreased irisin and myonectin; increased myostatin and IL-6), renokines (such as decreased Klotho; increased NGAL and renin), and osteokines (decreased osteocalcin; increased osteopontin and FGF-23), contributing to the pathophysiology of the syndrome.

Figure 6. Schematic representation of the interaction between MetS and organ-specific cytokine signaling. MetS, characterized by metainflammation, insulin resistance, visceral obesity, dyslipidemia, and hypertension, modulates and is modulated by the dysregulated secretion of different organokines. These include altered levels of cardiokines (e.g., decreased ANP, increased BNP, and GDF-15), adipokines (such as increased leptin, visfatin, and resistin; decreased adiponectin and omentin), myokines (such as decreased irisin and myonectin; increased myostatin and IL-6), renokines (such as decreased Klotho; increased NGAL and renin), and osteokines (decreased osteocalcin; increased osteopontin and FGF-23), contributing to the pathophysiology of the syndrome.

7. Integrated Model Linking MetS to Cardiovascular Disease

The adipo-myo-cardiac axis may include adipokines (leptin and resistin) and myokines (IL-6 and irisin) that regulate fatty acid oxidation and insulin sensitivity in muscle and the heart. Cardiokines (ANP and BNP) modulate the release of adiponectin by adipose tissue [24,25,71,72,83].

The bone-kidney-liver axis includes osteokines (osteocalcin and FGF-23) and rinokines (erythropoietin and Klotho) that regulate mineral metabolism, inflammation, and vascular function. FGF-23 (osteokine) and renin are linked to vascular calcification and hypertension in MetS [55,58,112].

The metabolic pattern in patients with MetS leads to systemic dysfunction of organokines. Hepatokines (such as Fetuin-A) and adipokines (such as leptin) exacerbate insulin resistance and hepatic steatosis [19,28,36]. Cardiokines and myokines (such as IL-6) contribute to cardiac dysfunction and muscle loss [41,79]. Osteokines (such as sclerostin) and rinokines (such as renin) promote hypertension and kidney disease [55,61].

As observed above, MetS is a result of a complex cross-talk among hepatokines, myokines, cardiokines, adipokines, rinokines, and osteokines. Dysfunctions in these axes promote an oxidative environment, chronic inflammation, insulin resistance, metabolic imbalance, and cardiometabolic complications.

The evidence summarized in this review supports an integrated model in which nutrient excess and adipose tissue expansion initiate metainflammation, leading to oxidative stress, mitochondrial dysfunction, and altered secretion of organokines. Mitochondrial impairment amplifies ROS production, ATP deficiency, mtDNA release, inflammasome activation, and endothelial dysfunction, while dysregulated adipokines, myokines, hepatokines, cardiokines, osteokines, and renokines propagate metabolic stress across organs. Gut microbiota dysbiosis and reduced SCFA production further weaken immunometabolic homeostasis. Together, these processes create a self-reinforcing network that links MetS to atherosclerosis, hypertension, insulin resistance, renal injury, hepatic steatosis, and cardiovascular disease progression.

8. Conclusions

MetS should be understood not merely as a cluster of cardiometabolic risk factors, but as a self-perpetuating network of metainflammation, mitochondrial dysfunction, oxidative stress, organokine imbalance, and microbial dysregulation. Metainflammation contributes to insulin resistance, vascular damage, and energy imbalance, ultimately promoting the onset and progression of cardiovascular disease. Mitochondrial dysfunction, a central feature of MetS, exacerbates ROS production, impairs ATP synthesis, and activates apoptotic and inflammatory signaling pathways, further exacerbating metabolic and cardiovascular imbalance. In this context, organokines, bioactive molecules secreted by the liver, muscle, adipose tissue, heart, bone, kidneys, and intestine, emerge as key inter-organ modulators for homeostasis or disease progression. Their dysregulated secretion promotes a pro-inflammatory, atherogenic, and insulin-resistant state. Furthermore, alterations in the gut microbiota, especially the reduction of short-chain fatty acids, disrupt immunometabolic homeostasis and contribute to the metabolic dysregulation observed in MetS. This integrated perspective shifts the focus from isolated metabolic abnormalities to interconnected signaling networks, supporting the development of biomarker-guided, multi-target, and organ-specific strategies for preventing cardiovascular complications in MetS.

9. Future Perspectives

Future research should move beyond single-pathway models of MetS and adopt multidimensional strategies that capture the interaction among metainflammation, mitochondrial dysfunction, organokine signaling, gut microbiota, and cardiovascular injury. First, organokines should be systematically evaluated as early biomarkers, diagnostic tools, and therapeutic targets, particularly in individuals transitioning from metabolically unhealthy obesity to overt cardiovascular disease. Second, mitochondrial-targeted interventions that restore redox balance, improve ATP synthesis, preserve mtDNA integrity, and limit inflammasome activation deserve further translational investigation. Third, modulation of gut microbiota composition and SCFA production may provide an additional strategy to restore immunometabolic homeostasis.

Systems biology, multi-omics profiling, and network-based approaches will be essential for mapping the crosstalk among adipose tissue, skeletal muscle, liver, heart, bone, kidney, and intestine [https://doi.org/10.3390/biomedicines14010159; https://doi.org/10.3390/biomedicines14010035; https://doi.org/10.3390/ijms262010238]. Clinical trials should test combined interventions, including exercise, dietary modulation, microbiota-directed therapies, and agents targeting FGF-21, myostatin, adiponectin, or related organokine pathways. Ultimately, personalized cardiometabolic medicine may help identify patient subgroups that benefit from systemic versus organ-specific interventions, improving therapeutic efficacy while minimizing adverse effects.