Targeting Metainflammation in Hidradenitis Suppurativa: The Emerging Role of GLP-1 Receptor Agonists and Metabolic Pharmacotherapies

1. Background

Hidradenitis suppurativa (HS) is a chronic immunometabolic skin disease with systemic manifestations that extend well beyond the cutaneous lesions [70]. Patients with HS frequently present with key metabolic and cardiovascular comorbidities, including type 2 diabetes, metabolic syndrome (MetS), metabolic dysfunction-associated steatotic liver disease, and polycystic ovary syndrome [68,87]. While the primary etiology of HS remains incompletely understood, initial lesion development is widely recognized to center on the pilosebaceous unit, driven by infundibular hyperkeratosis, follicular occlusion, and subsequent follicular rupture [93]. Rupture of the hair follicle releases damage-associated molecular patterns and pathogen-associated molecular patterns into the dermis, initiating the activation of Toll-like receptors (TLRs), particularly TLR2 and TLR4, on dermal dendritic cells and macrophages [49,109]. In vitro and lesional tissue studies have demonstrated that Toll-like receptor activation triggers nuclear factor kappa B (NF-κB)-mediated transcription and recruits the factor kappa B (NF-κB) and NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome; promoting the release of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) [4,75]. Furthermore, high local glucose availability and insulin resistance are mechanistically hypothesized to suppress keratinocyte antimicrobial peptide (AMP) expression, with dysregulated human beta-defensin 2 (hBD-2) and cathelicidin (LL-37) levels being associated with follicular bacterial overgrowth and wall destabilization in HS [84,102].

Following this initial innate immune activation and bacterial overgrowth, rapid neutrophil recruitment drives cellular breakdown, tissue destruction, and purulence, contributing to the generation of painful nodules and abscesses [12]. Downstream adaptive immune responses involve T-helper 17 (Th17) cell polarization, with hypersecretion of interleukin-17A (IL-17A) and interleukin-17F (IL-17F) being associated with matrix metalloproteinase induction (MMP-2, MMP-8, and MMP-9), structural tissue destruction, and tunnel formation in HS [72]. Universal pathogenic pathways across patients with HS have not been established, while substantial immunological heterogeneity and the resulting variability in treatment response are widely recognized [31]. Furthermore, follicular occlusion and downstream cutaneous inflammation are increasingly recognized as processes that are potentially amplified by systemic metabolic dysregulation and meta-inflammation [20]. Cross-sectional population studies demonstrate that the elevated prevalence of MetS in patients with HS remains statistically significant even among patients with a normal BMI, with an odds ratio (OR) of 1.45 (compared with an OR of 1.60 in patients with HS and severe obesity) [87]. Notably, normal-weight patients with HS display higher visceral adiposity, elevated triglycerides, and increased Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) compared with matched controls, supporting a distinct metabolically unhealthy normal-weight phenotype [69]. Mechanistically, hyperinsulinemia is further suggested to activate the mammalian target of rapamycin complex 1 (mTORC1) and suppress the nuclear transcription factor forkhead box protein O1 (FoxO1) in keratinocytes, promoting infundibular hyperplasia and epidermal thickening [74,107].

Figure 1. Pathogenic Continuum of Follicular Occlusion, Rupture, and Metainflammatory Adipokine Crosstalk in Hidradenitis Suppurativa. Schematic representation of the multi-stage immunometabolic pathogenesis of hidradenitis suppurativa. Normal Hair Follicle and Hyperkeratosis/Plugging: Baseline infundibular architecture progresses to hyperkeratosis and follicular plugging, driven by hyperinsulinemia, mTORC1 activation, FoxO1 suppression, and continuous upward secretion of pro-inflammatory adipocytokines from underlying subcutaneous fat. Follicular Rupture and Innate Sensing: Follicular occlusion leads to luminal distension and rupture, releasing microbial pathogen-associated molecular patterns (PAMPs) and tissue-derived damage-associated molecular patterns (DAMPs) into the dermis, engaging Toll-like receptors (TLRs) and triggering NF-κB activation. Inflammation Stage and Clinical Features: Downstream NF-κB and inflammasome activation drives the secretion of TNF-α, IL-1β, IL-23, and IL-17, recruiting neutrophils, macrophages, Th1/Th17 lymphocytes, and B-cells to promote intense dermal inflammation, culminating in painful nodule and deep abscess formation.

Figure 1. Pathogenic Continuum of Follicular Occlusion, Rupture, and Metainflammatory Adipokine Crosstalk in Hidradenitis Suppurativa. Schematic representation of the multi-stage immunometabolic pathogenesis of hidradenitis suppurativa. Normal Hair Follicle and Hyperkeratosis/Plugging: Baseline infundibular architecture progresses to hyperkeratosis and follicular plugging, driven by hyperinsulinemia, mTORC1 activation, FoxO1 suppression, and continuous upward secretion of pro-inflammatory adipocytokines from underlying subcutaneous fat. Follicular Rupture and Innate Sensing: Follicular occlusion leads to luminal distension and rupture, releasing microbial pathogen-associated molecular patterns (PAMPs) and tissue-derived damage-associated molecular patterns (DAMPs) into the dermis, engaging Toll-like receptors (TLRs) and triggering NF-κB activation. Inflammation Stage and Clinical Features: Downstream NF-κB and inflammasome activation drives the secretion of TNF-α, IL-1β, IL-23, and IL-17, recruiting neutrophils, macrophages, Th1/Th17 lymphocytes, and B-cells to promote intense dermal inflammation, culminating in painful nodule and deep abscess formation.

In parallel, emerging insights into the role of adipose tissue have expanded beyond its function as a simple energy storage depot, with adipose tissue now recognized as an active endocrine organ that secretes bioactive signaling peptides termed adipokines and cytokines, which serve as key mediators of systemic inflammation and metabolic crosstalk [30,103]. In healthy subcutaneous fat, anti-inflammatory M2 macrophages predominate to maintain tissue tolerance. In obesity and, potentially, in HS, adipose tissue undergoes immunological remodeling, in which accumulating pro-inflammatory M1 macrophages and CD8+ cytotoxic T cells drive the release of pro-inflammatory mediators (TNF-α, IL-6, and interferon-gamma) that promote the pathogenic IL-23/Th17 axis and exacerbate cutaneous disease activity [57,65]. Importantly, cross-sectional cohort studies in patients with HS confirm that several alterations in adipokine profiles remain statistically significant after adjustment for BMI, indicating that adipokine dysregulation might be linked to HS pathophysiology independently of increased BMI [65]. Currently, guidelines for moderate-to-severe HS recommend a stepped therapeutic approach that combines topical treatments, systemic antibiotics, and targeted biologics. However, clinical responses remain insufficient for many patients [116]. While guidelines acknowledge lifestyle modifications, weight management, and metformin as general adjuvant measures, detailed guidance on how to integrate and differentiate between distinct metabolic pharmacotherapies remains limited [11,116]. Further synthesis is needed to determine how individual metabolic agents, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), GLP-1RA multi-agonists, metformin, sodium–glucose cotransporter 2 inhibitors (SGLT-2is), and peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists, can be selected according to patient phenotypes and combined with conventional therapies. This narrative review synthesizes clinical and mechanistic evidence supporting the positioning of these distinct metabolic pharmacotherapies in the management of HS.

2. Methods

This narrative review was prepared in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA) [6]. PubMed and Embase were searched on 28 March 2026 using key terms related to hidradenitis suppurativa ("hidradenitis suppurativa", "acne inversa", "follicular occlusion", "hurley*"); obesity, adipokines, and metabolic dysfunction ("obesity", "adiposity", "body mass index", "metabolic syndrome", "insulin resistance", "type 2 diabetes mellitus", "leptin", "adiponectin", "retinol-binding protein 4", "haptoglobin"); and metabolic pharmacotherapies (GLP-1 receptor agonists and individual agents, dual GLP-1/GIP agonists, tirzepatide, retatrutide, SGLT-2 inhibitors, metformin, pioglitazone). The search yielded 1,140 records; after deduplication, 985 records were screened by title and abstract, 148 underwent full-text assessment, and 42 were included. Studies reporting original HS-specific outcomes following metabolic interventions or investigating relevant metabolic-inflammatory mechanisms were eligible for inclusion. An additional 75 articles were identified through reference checking, Google Scholar, and targeted database searches, bringing the total number of articles included in the narrative synthesis to 117. Preclinical, in vitro, and non-HS clinical studies were explicitly identified as such in the text. (Supplementary 1)

3. Metabolic Dysfunction and Systemic Markers

3.1. Dysfunctional Adipose Tissue and Adipokines

Adipose tissue is increasingly recognized as an active endocrine and immunological organ rather than a passive energy storage depot [29,48]. HS, obesity and MetS are associated with structural remodeling of visceral and subcutaneous adipose tissue and a shift in its secretory profile, characterized by dysregulated release of bioactive peptides, adipokines, and pro-inflammatory cytokines that potentially support local and systemic inflammatory feedback loops [20,57]. The pathological alterations in adipose tissue architecture, immune cell infiltration, and secretory output are schematically illustrated in Figure 2.

Multiple adipokines have been demonstrated in clinical case-control studies to be dysregulated in HS, with each fulfilling a distinct pathophysiological role, as summarized in Table 1. Notably, circulating leptin levels correlate strongly with BMI (r = 0.83) and activate Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3)-driven Th17 polarization, whereas adiponectin depletion occurs independently of BMI, removing a critical 5′-AMP-activated protein kinase (AMPK)-mediated brake on NF-κB signaling [36,65]. Both resistin and visfatin have been identified as independent risk factors for HS development independently of BMI, age, and sex, although neither correlates with Hurley HS severity stage [3,36]. Omentin-1 is paradoxically elevated in HS despite being anti-inflammatory in non-HS populations; potentially attributed to omentin-1’s enhancement of cutaneous IL-1β signaling, thereby amplifying neutrophil recruitment and tunnel formation [34]. Circulating chemerin levels are elevated in HS and act as a potent chemoattractant, recruiting plasmacytoid dendritic cells and neutrophils to lesional skin via Chemokine-like receptor 1 (CMKLR1). [57] Finally, Retinol-binding protein 4 represents a distinctive link between cutaneous severity and metabolic dysfunction, as it correlates with both Hurley stage and HOMA-IR independently of BMI [35].

Beyond adipokines, expanding adipose tissue in HS undergoes immunometabolic remodeling characterized by infiltration by M1 macrophages and elevated secretion of TNF-α, IL-6, IL-1β, and Monocyte chemoattractant protein-1 [48,57]. In obesity and type 2 diabetes studies, adipose-derived TNF-α has been shown to impair peripheral insulin receptor substrate-1 signaling via JNK-mediated serine phosphorylation, a mechanism that is hypothesized to contribute to the systemic insulin resistance observed in HS [48,107]. Furthermore, saturated free fatty acids released from adipocytes function as endogenous damage-associated molecular patterns (DAMPs) that initiate TLR4 signaling, amplifying IL-1β release [57,96].

3.2. Systemic Metabolites, Acute-Phase Reactants, and Gut-Derived Mediators

Moving from adipokines and cytokines, HS is additionally characterized by dysregulation of systemic metabolites, including acute-phase reactants, and gut microbiome-derived mediators that have been associated with both cutaneous inflammation and systemic metabolic comorbidities (summarized in Table 2). Among acute-phase markers, Abu Rached et al. [89,90] demonstrated that serum haptoglobin serves as a strong independent serological predictor of Hurley stage III disease and metabolic complications, with elevated levels being associated with reduced pancreatic β-cell compensation and elevated HbA1c. The pan-immune-inflammation value (PIV), calculated as increases progressively across Hurley stages and is independently associated with comorbid metabolic syndrome (OR 1.41) [45]. Likewise, the heparin-binding growth factor midkine correlates positively with waist circumference, triglycerides, and diastolic blood pressure [15]. The systemic involvement in HS is further supported by altered circulating amino acid profiles (e.g., branched-chain amino acids, phenylalanine, and tyrosine) and markedly elevated levels of trimethylamine N-oxide (TMAO), a gut microbiota-derived hepatic metabolite that has been shown to correlate strongly with Sartorius severity scores (r = 0.570) in HS [8,108].

Genomic sequencing studies in HS cohorts demonstrate shifts in the gut microbiome, characterized by a relative depletion of anti-inflammatory members of the Firmicutes, a major bacterial group that constitutes a substantial part of the human gut flora and includes short-chain fatty acid-producing bacteria [60]. The resulting depletion of short-chain fatty acids (SCFAs) is proposed to compromise epithelial tight junction integrity [60], facilitating the translocation of gut-derived lipopolysaccharide (LPS) into the bloodstream [72]. Circulating LPS subsequently engages Toll-like receptor complexes on immune cells, triggering NF-κB activation and amplifying systemic TNF-α, IL-1β, and IL-17 signaling [72]. Interestingly, adalimumab (anti-TNF-α) has also been shown to modulate gut microbiome composition and restore fecal SCFA levels in treated patients, independently of the cutaneous clinical response [101].

Additionally, a link has been proposed between host-microbiota catabolism of tryptophan, an essential amino acid, and HS pathophysiology. Guenin-Macé et al. (2020) mapped the biochemical and microbiological roles of tryptophan in HS, demonstrating that localized overactivation of the kynurenine pathway in lesional skin is accompanied by significantly reduced plasma tryptophan levels in patients with HS [38]. In the cutaneous microenvironment, inflammatory cytokines induce local overactivation of the enzymes Indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase, shunting tryptophan down the kynurenine pathway and reducing protective indole metabolites (such as indole-3-acetic acid) produced by resident skin bacteria, thereby directly compromising epidermal barrier integrity and immune homeostasis [38,98]. Collectively, these systemic metabolic, acute-phase, and microbiome-associated alterations underscore the broad immunometabolic involvement in HS, reinforcing the rationale for integrating metabolic interventions and biomarker monitoring (Table 2).

4. Metabolic Pharmacotherapies Relevant for HS

4.1. Glucagon-Like Peptide-1 Receptor Agonists

GLP-1RAs exert pleiotropic effects through multi-organ pathways, with emerging evidence suggesting additional direct immunomodulatory effects [25,46,50]. Centrally, GLP-1RAs activate pro-opiomelanocortin/cocaine- and amphetamine-regulated transcript (POMC/CART) neurons within hypothalamic satiety centers while suppressing neuropeptide Y/agouti-related peptide (NPY/AgRP) signaling to regulate appetite and enhance satiety [25,71]. Modulating central reward circuits might be of particular therapeutic interest in HS, as chronic pain, systemic inflammation, and psychological distress frequently drive reward-driven and emotional eating behaviors, disordered eating patterns (such as binge eating disorder), and severely impaired health-related quality of life [22,77,92].

Systemically and peripherally, GLP-1 receptor activation enhances glucose-dependent pancreatic β-cell insulin secretion and improves peripheral insulin sensitivity, supporting the attenuation of systemic metainflammation [39,46]. High-dose, obesity-targeted GLP-1RAs induce substantial body weight reduction (e.g., 10–15% mean weight loss with semaglutide 2.4 mg weekly in the STEP 1 trial [112]. In patients with HS, weight loss potentially helps reduce mechanical skin-on-skin friction, maceration, and follicular shear stress in intertriginous skin areas [10,50,99]. Crucially, reducing visceral adiposity is proposed to favorably modulate the dysregulated adipokine profile in HS by decreasing pro-inflammatory adipose tissue, immune cell infiltration, and suppressing circulating levels of pro-inflammatory adipokines, while elevating anti-inflammatory adiponectin [57,73]. These metabolic changes, accompanied by a reduction in systemic acute-phase reactants [78,90], is hypothesized to reduce the systemic metabolic drivers promoting cutaneous follicular hyperkeratosis, follicular occlusion, and subsequent lesion rupture. The multi-organ physiological actions of GLP-1RA therapy are presented in Figure 3.

Direct cutaneous GLP-1 receptor expression on human dermal keratinocytes and sebocytes remains controversial. While preliminary in vitro models suggested direct GLP-1 receptor signaling, human tissue studies in psoriasis plaque biopsies suggest that GLP-1 receptor gene expression is localized primarily to infiltrating immune cells (such as Invariant natural killer T cells) rather than resident epidermal keratinocytes [28,44]. Thus, direct weight-independent cutaneous immunomodulation in human HS skin remains uncertain. Regarding the gut-skin axis, GLP-1 receptor signaling on intestinal intraepithelial lymphocytes represents a physiologically plausible translational model to support mucosal barrier function and potentially reduce systemic translocation of gut-derived LPS [7,100] , though direct measurements of intestinal permeability following GLP-1RA therapy in human HS cohorts remain lacking.

The clinical evidence base for GLP-1RAs in HS has expanded recently. A comprehensive systematic review by Visan et al. [106] encompassing 19 studies and over 67,000 patients with HS demonstrated clinical improvements in Hurley stage, International Hidradenitis Suppurativa Severity Score System (IHS4), pain scores, and Dermatology Life Quality Index (DLQI), complemented by nationwide retrospective cohort analyses by Jastrząb-Miśkiewicz et al. [53] and other large-scale TriNetX registry studies showing significant reductions in all-cause mortality, major adverse cardiovascular events, emergency department visits, surgical interventions, and systemic antibiotic prescriptions [40,53,63]. Smaller prospective and observational cohorts (e.g., Gouvrion et al., 2025 [n=66]; Lyons et al., 2024 [n=30]; Nicolau et al., 2024 [n=14]) further confirm meaningful dermatological improvements [37,62,78]. Nevertheless, under the Oxford Centre for Evidence-Based Medicine (OCEBM) framework, the overall evidence remains Level 4 due to the complete lack of published randomized controlled trials (RCTs) [5,106]. Gastrointestinal adverse events (nausea, vomiting, diarrhea) represent the primary tolerability challenge, requiring gradual dose escalation [76,85], while financial cost, financial coverage barriers, and potential rebound weight regain upon treatment cessation represent notable real-world clinical challenges [71,106]. Consequently, so far, clinical studies suggest positioning GLP-1RAs as an adjuvant metabolic therapy alongside established biologics and surgical interventions to optimize drug bioavailability and long-term disease control, rather than as a standalone HS monotherapy [5,106].

4.2. Next-Generation Multi-Receptor Agonists

Multi-receptor agonists extend beyond selective GLP-1 mono-agonism by co-targeting complementary metabolic pathways to achieve broader immunometabolic effects [52,53]. Dual GLP-1/ Glucose-dependent insulinotropic polypeptide (GIP) agonists, such as tirzepatide, activate both GLP-1 and GIP receptors [50]. In addition to GIP's native incretin function of stimulating pancreatic insulin secretion [46], GIP signaling in subcutaneous adipose tissue is proposed to enhance lipid storage capacity, thereby helping to prevent ectopic lipid accumulation while synergizing with GLP-1 to achieve superior weight loss compared with mono-agonists [94]. By more effectively reducing visceral adiposity, dual agonists are hypothesized to suppress M1 macrophage infiltration and reduce circulating pro-inflammatory adipokines (leptin, resistin) that may otherwise fuel cutaneous inflammation, while superior weight loss directly alleviates mechanical intertriginous friction [10,114].

Clinical evidence for multi-receptor agonism in HS is still emerging and remains at Level 4 (OCEBM) [106]. In a landmark report by Chan et al. (2024), weekly tirzepatide treatment in a patient with severe, biologic-refractory HS, type 2 diabetes, and obesity induced rapid clinical improvement (Hidradenitis Suppurativa Physician’s Global Assessment from severe to mild, reduced abscesses, and improved DLQI), alongside normalization of hemoglobin A1c (HbA1c) and triglyceride levels over 3 months [16]. Data from the completed open-label pilot study (NCT06301256) evaluating tirzepatide for moderate-to-severe HS showed a 80% HiSCR rate after 24 weeks [1]. Additionally, the triple agonist retatrutide (GIP/GLP-1/glucagon) co-targets glucagon receptors to stimulate hepatic lipid clearance and thermogenesis, achieving >24% weight loss and marked reductions in hepatic fat and fibrosis in Phase 2 trials [52,95]. While promising for severe, refractory phenotypes, long-term dermatological trials evaluating structural tunnel outcomes remain limited, supporting the role of these agents a Level 4 to 5 OCEBM investigational adjuncts [106].

4.3. Biguanide Therapy: Metformin

Metformin is hypothesized to exert multifaceted immunometabolic effects relevant to HS pathogenesis [18,54].

• AMPK Activation and mTORC1 Suppression: Metformin reversibly inhibits mitochondrial respiratory complex I, elevating intracellular Adenosine monophosphate/adenosine triphosphate (AMP/ATP) ratios to activate AMPK [83]. AMPK directly inhibits hyperactive mTORC1 and sterol regulatory element-binding protein 1c signaling, suppressing infundibular keratinocyte proliferation, follicular hyperkeratosis, and sebaceous lipogenesis [18,107].
• NLRP3 Inflammasome Blockade: AMPK activation promotes mitochondrial autophagy and reduces mitochondrial reactive oxygen species production, blunting NLRP3 inflammasome assembly and pro-IL-1β cleavage [86].
• Androgen and Hyperinsulinemia Reduction: By suppressing hepatic gluconeogenesis and enhancing muscle glucose uptake, metformin lowers circulating insulin, reducing ovarian and adrenal androgen production (testosterone, Dehydroepiandrosterone sulfate) in female patients with HS and comorbid PCOS [22,43].
• Metabolic Reprogramming (Warburg Shift): Metformin inhibits dysregulated aerobic glycolysis (Warburg effect) in lesional peripheral blood mononuclear cells and dermal macrophages, restoring cellular bioenergy and reducing inflammatory chemokines in HS tunnels and inflammatory nodules [86].
• Pharmacomicrobiomics and AMP Restoration: Metformin may alter the composition of the gut microbiome (e.g., enriching intestinal Akkermansia muciniphila) and reduce circulating endotoxins [83]. Furthermore, by improving local epidermal glucose handling and reducing systemic meta-inflammation, metformin is hypothesized to support the restoration of endogenous antimicrobial peptide secretion by keratinocytes (LL-37, hBD-2) [59,84].

Metformin has the longest-established observational clinical evidence base among metabolic therapies in HS. Verdolini et al. [105] documented significant clinical improvement in 72% of 25 patients receiving metformin (500–1500 mg/day), with a mean reduction in Sartorius score of 12.7 points, while Jennings et al. [55] reported a 68% subjective clinical response rate in a cohort of 53 patients (with 19% achieving complete disease remission on monotherapy). A comprehensive systematic review by Almukhadeb et al. [5] confirmed an overall clinical response rate of 68-75% across observational cohorts, with optimal efficacy observed in female patients presenting with insulin resistance, elevated HOMA-IR, or comorbid PCOS. Importantly, metformin is approved for pediatric metabolic dysfunction from the age of 10 years, supporting early intervention in adolescent HS [83].

The primary limitation of metformin is gastrointestinal intolerance (diarrhea, abdominal cramps, flatulence) during treatment initiation [55,105]. Metformin produces only modest weight loss (2–5%) [5]. During long-term use, periodic monitoring of vitamin B12 levels is recommended [19]. While observational prospective series and retrospective cohorts (OCEBM Level 4) support metformin as a low-cost intervention [5,105], recent Phase III randomized controlled trial data indicate that metformin combined with doxycycline was not clinically superior to doxycycline monotherapy in terms of primary cutaneous outcomes, highlighting the need for cautious interpretation [81].

4.4. Sodium–Glucose Cotransporter 2 Inhibitors

SGLT-2is (e.g., empagliflozin, dapagliflozin) lower blood glucose by selectively inhibiting renal tubular glucose reabsorption in the proximal convoluted tubule, independent of insulin secretion [115]. The resulting glucosuria causes a modest caloric loss (typically leading to a 2–3 kg weight reduction) and a metabolic shift toward ketogenesis [82]. At the cellular level, SGLT-2is may suppress NLRP3 inflammasome activation, reduce serum uric acid, and attenuate oxidative stress in vascular endothelial cells [111]. Additionally, SGLT-2i therapy has been proposed to reduce key markers of systemic vascular inflammation and tissue fibrosis, including circulating TNF-α and IL-6 [42]. This cardiorenal and anti-inflammatory profile is particularly relevant to patients with HS, as studies demonstrate a significantly elevated baseline risk of cardiovascular morbidity, heart failure, and chronic kidney disease [88,91]. SGLT-2is provide guideline-supported cardiorenal protection in high-risk cardiometabolic cohorts, reducing heart failure hospitalizations and slowing renal disease progression [66]. In the only large-scale HS-specific study to date, Cheng et al. [17] conducted a population-based cohort study of 3,394 patients with HS and concomitant type 2 diabetes and found that SGLT-2i treatment, over a mean follow-up of six years, was associated with a significantly decreased risk of obesity, all-cause mortality, emergency department visits, and major cardiorenal complications compared with propensity score-matched GLP-1RA users.

However, clinical implementation requires careful patient selection. SGLT-2i therapy is associated with a well-documented 5–10% increased risk of genital mycotic infections (e.g., vulvovaginal candidiasis, balanitis) due to drug-induced glucosuria [111]. This warrants careful evaluation in patients with HS who have active perineal, inguinal, or gluteal lesions because local maceration and bacterial and fungal coinfections may exacerbate disease burden. Furthermore, clinicians should also consider rare but life-threatening risks, including euglycemic diabetic ketoacidosis and perineal necrotizing fasciitis (Fournier’s gangrene), as well as a potential registry-associated risk of paradoxical psoriasis flares [9,21,64,111].

Consequently, while SGLT-2is possess OCEBM Level 4 evidence for reducing systemic and cardiorenal risk in patients with HS and concomitant T2DM [17], prospective randomized controlled trials evaluating HS-specific cutaneous primary endpoints are lacking, leaving evidence for their direct dermatological efficacy at Level 5 [5,111].

4.5. Peroxisome Proliferator-Activated Receptor-γ Agonists: Pioglitazone

Pioglitazone is a thiazolidinedione that acts as a potent agonist of the nuclear receptor PPAR-γ [23]. In preclinical models, PPAR-γ activation in subcutaneous adipocytes and dermal macrophages promotes adipocyte differentiation, enhances fatty acid storage, and markedly upregulates serum adiponectin [57,70]. Elevated adiponectin is mechanistically plausible as an activator of cutaneous AMPK, suppressing NF-κB transcription and downregulating TNF-α, IL-1β, and IL-6 release from dermal dendritic cells and macrophages in vitro [57,70]. Therapeutically, pioglitazone is hypothesized to be a potential investigational adjunct in HS patients presenting with comorbid metabolic dysfunction-associated steatotic liver disease or severe peripheral insulin resistance without marked obesity [70]. However, clinical translation is constrained by significant safety considerations. Pioglitazone is known to induce renal sodium reabsorption in the collecting duct via PPAR-γ-mediated activation of epithelial sodium channels, leading to fluid retention and peripheral edema [23]. This fluid accumulation leads to a secondary increase in total body weight; however, this fluid-driven weight gain must be clearly distinguished from adipose mass accumulation, as plasma volume expansion poses distinct hemodynamic risks. Because fluid overload increases cardiac preload, pioglitazone is contraindicated in patients with heart failure, a crucial safety consideration given the elevated baseline risks of cardiovascular disease and heart failure observed in HS cohorts [23,26]. Additionally, long-term PPAR-γ activation is associated with bone loss, hypothesized to stem from a shift in mesenchymal stem cell differentiation away from osteoblasts toward adipocytes, thereby accelerating bone turnover and increasing fracture risk [23]. Currently, no published human clinical trials or prospective case series have evaluated pioglitazone in HS cohorts; its evidence base remains restricted to Level 5 (preclinical hypotheses and pathophysiological alignment) [70].

5. Discussion

5.1. Metainflammation as a Driver and Structural Integration

HS has traditionally been conceptualized as a primary inflammatory disorder. However, accumulating translational and epidemiological evidence supports an emerging paradigm shift: metabolic dysregulation, visceral adipose tissue dysregulation, and systemic metainflammation potentially function as active drivers of disease pathogenesis [32,57]. Visceral adipose tissue dysregulation is proposed to impact dermal inflammation and scar formation through alterations in the adipokine axis, characterized by elevated leptin, resistin, visfatin, and Retinol-binding protein 4 alongside suppressed adiponectin (Summarized in Table 1). These adipokine alterations occur alongside alterations in haptoglobin, high-sensitivity C-reactive protein, PIV, TMAO, and short-chain fatty acid profiles (Summarized in Table 2). Crucially, these metabolic elements appear to contribute to HS, at least partially, independently of BMI, as metabolically unhealthy normal-weight phenotypes have been described [69]. This conceptual reframing establishes a rationale for integrating metabolic pharmacotherapies into HS therapeutic regimens. Cytokine-targeted biologics (e.g., adalimumab, secukinumab, bimekizumab) suppress specific pathways, whereas metabolic pharmacotherapies target underlying metabolic contributors or initiators [5]. Table 3 contextualizes these distinct pharmacological classes, establishing their potential and suggested roles in terms of levels of evidence and weight dependence and in relation to specific HS phenotypes and comorbidities.

5.2. The Epidermal Barrier-Mitochondrial-Microbiota Axis and Local Immunometabolic Mechanisms

Additionally, recent translational studies reframe HS as a disorder of impaired local innate immunosurveillance, establishing a link between microbial invasion, autoinflammation, and humoral autoimmunity [2,13,14]. Agbogan et al. [2] demonstrated that Porphyromonas uenonis, an anaerobic bacterium selectively enriched in active skin lesions from patients with HS, actively penetrates an intact epidermal barrier, infects primary keratinocytes, and triggers pro-inflammatory cytokine cascades. Additionally, P. uenonis invasion is associated with local epidermal IgA deposits, while patient-derived anti-P. uenonis IgG antibodies cross-react with self-antigens (such as lysozyme) expressed by healthy keratinocytes, linking localized dysbiosis to systemic humoral autoimmunity [2]. In parallel, Carmona-Rivera et al. [14] established that lesional IgA and IgG autoantibodies in HS skin form immune complexes that engage macrophage Fc receptors, promoting dermal inflammation, matrix degradation (MMP-2, MMP-9), and fibrotic scarring. Mitochondrial dysfunction has also been suggested as a potential bioenergetic factor contributing to this epidermal barrier vulnerability, thereby providing a possible link between these bacterial and immunological mechanisms and metabolic dysfunction. Transcriptomic profiling via gene set enrichment analysis reveals that mitochondrial oxidative phosphorylation is among the most downregulated biochemical pathways across both lesional and clinically uninvolved HS skin [47,80,98]. Systemic hyperinsulinemia and local glucose excess are hypothesized to exacerbate this defect by suppressing keratinocyte secretion of endogenous antimicrobial peptides (such as hBD-2), thereby weakening the chemical barrier shield [47,84]. Interestingly, GLP-1RAs (e.g., semaglutide) have been proposed as potential modulators of mitochondrial stress [47]. As suggested in the conceptual framework of Delage et al. [24], HS is best understood as a heterogeneous spectrum spanning autoinflammatory hyper-reactivity, localized autoinfection, and partial innate immunodeficiency [24,109].

5.3. Endocrine-Metabolic Crosstalk, Anti-Androgen Synergy, and Pharmacokinetic Rescue

Observations in female HS cohorts contribute to the understanding that metabolic dysregulation is not exclusively driven by obesity. PCOS affects up to 22.3% of female patients with HS, and insulin resistance is present in 43.4–77% of patients across cohorts, regardless of BMI [5,110]. Metformin is suggested to modulate this neuroendocrine axis in HS by lowering circulating IGF-1, elevating IGFBP-1, activating FoxO1, and inhibiting key steroidogenic enzymes (CYP17A1, HSD3B2), thereby suppressing mTORC1 hyperactivation and keratinocyte infundibular hyperkeratosis [5,116].

Because hyperinsulinemia directly stimulates ovarian and adrenal androgen synthesis, co-prescribing metformin or GLP-1RAs alongside anti-androgenic agents (e.g., spironolactone, finasteride) creates a potential dual-target synergy: metabolic agents target the upstream endocrine driver (hyperinsulinemia), while anti-androgens block downstream end-organ receptor sensitivity in the relevant HS patient phenotype [56,110,116].

Furthermore, metabolic interventions may address potential pharmacokinetic challenges in the treatment of patients with obesity and HS. Studies in HS suggest that higher BMI is associated with increased monoclonal antibody clearance and lower concentrations of biologics, whereas weight loss may improve drug exposure by reducing the volume of distribution and clearance, potentially supporting treatment efficacy and biologic persistence [61,79]. Additionally, differences between diabetes-targeted and obesity-targeted dosing regimens have been discussed in the literature: higher obesity-targeted doses appear to yield greater cutaneous responses, although clinical improvements have also been reported with lower diabetes-targeted doses [5,33]. Exact comparative dosing trials and standardized clinical dosing guidelines in HS are currently lacking.

5.4. The Three-Pillar Multimodal Model

To integrate these immunometabolic insights into routine practice, a structured three-pillar multimodal treatment model can be considered:

• Antimicrobial Modulation: Systemic antibiotics (clindamycin/rifampicin, tetracyclines) are proposed to address active follicular dysbiosis and suppress anaerobic pathogens (P. uenonis); certain agents also possess anti-inflammatory properties [116].
• Cytokine Blockade: Targeted biologics (adalimumab, secukinumab, bimekizumab) aim to rapidly suppress inflammatory cytokines, thereby targeting immune responses and inflammation involved in HS pathogenesis [116].
• Metabolic Pharmacotherapy: Incretin therapies (GLP-1RAs, tirzepatide) and biguanides (metformin) are suggested to target underlying metainflammation, support mitochondrial bioenergetics and AMP secretion, relieve mechanical intertriginous friction, and optimize biologic pharmacokinetics [47,77].

A critical evaluation of the evidence hierarchy reveals key methodological limitations across the field (Table 3). Metformin possesses an established observational record [41,105], yet a Phase III RCT (n=135) demonstrated that metformin combined with doxycycline was not superior to doxycycline monotherapy for primary cutaneous outcomes, underscoring the need for controlled validation [81]. GLP-1RA evidence encompasses pooled systematic reviews [106] and nationwide cohorts [53,97], but remains limited by retrospective designs and selection bias. Furthermore, reliance on static Hurley staging rather than dynamic IHS4/HiSCR metrics represents a recurring methodological limitation across metabolic intervention studies in HS. Evidence for dual agonists (Level 4), triple agonists (Level 5), SGLT-2 inhibitors (Level 4-5), and pioglitazone (Level 5) currently remains restricted to case series and translational extrapolation. Finally, clinical timing and interdisciplinary collaboration are essential. Initiating systemic metabolic therapies early in the disease course may be valuable before rescue surgery for fixed, scar-dominated lesions becomes necessary [58]. Crucially, dermatologists typically encounter patients with HS at an earlier age and disease stage, which provides an optimal window for implementing preventive metabolic interventions, whereas consultations in cardiology or endocrinology clinics often occur during later stages of cardiometabolic progression [32,116]. Utilizing composite metabolic and inflammatory biomarkers, such as HOMA-IR, high-sensitivity C-reactive protein, PIV, and adipokine profiles, provides a potential practical tool for future clinical screening, monitoring treatment response, and stratifying cardiovascular risk in patients with HS [32,117].

6. Conclusions

Current evidence demonstrates that metabolic dysregulation in HS functions as an active pathogenic driver rather than a passive comorbidity. Integrating validated clinical severity scores (IHS4) with systemic inflammatory markers (hs-CRP, haptoglobin, PIV and metabolic profiles (HOMA-IR, adiponectin/leptin ratio) provides a future potential framework for transitioning from empirical immunosuppression to phenotype-driven precision medicine. Combining targeted biologics with metabolic pharmacotherapies represents relevant future therapeutic strategies for achieving long-term disease modification in specific immunometabolic phenotypes in HS.