INTRODUCTION

Metabolic liver diseases encompass a spectrum of conditions historically referred to as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In 2020, metabolic dysfunction-associated fatty liver disease (MAFLD) was introduced to more explicitly reflect the central role of metabolic impairment in disease pathogenesis. More recently, major hepatology societies have endorsed the terminology metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) as the preferred and unified framework, replacing NAFLD/NASH and superseding MAFLD. Together, these metabolic liver diseases represent some of the most common and clinically significant causes of chronic liver injury worldwide [1]. MASLD represents a continuum, from simple hepatic steatosis to steatohepatitis and advanced fibrosis, which may progress to cirrhosis or hepatocellular carcinoma, and affects more than one-third of adults globally. The increasing prevalence of MASLD is driven by obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and gut dysbiosis, emphasizing the need to address metabolic comorbidities toward halting disease progression [2,3]. Recent advances in the field include the establishment of a unified nomenclature, U.S. Food and Drug Administration approval of resmetirom for treating noncirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis, and a growing consensus on the need for validated noninvasive biomarkers and risk-stratification tools to facilitate earlier detection and accelerate therapeutic development [4].

At the cellular level, hepatic dysfunction in metabolic diseases arises from a combination of insulin resistance [5,6], lipotoxic stress, inflammation [7], and mitochondrial dysfunction [8]. Insulin resistance increases hepatic gluconeogenesis and de novo lipogenesis, leading to triglyceride accumulation and endoplasmic reticulum (ER) stress [9]. Excess free fatty acids and their toxic intermediates disrupt calcium (Ca²⁺) homeostasis and generate reactive oxygen species (ROS), which together promote inflammation, hepatocellular injury, and fibrosis [10,11]. This metabolic-inflammatory axis is central to the transition from simple steatosis to MASH [12].

Recent advances have expanded the therapeutic landscape of metabolic liver diseases to include agents that modulate systemic metabolism beyond traditional hepatic targets [13]. Among these, sodium-glucose cotransporter 2 (SGLT2) inhibitors have attracted particular attention [14,15]. Originally introduced for glycemic control in T2DM through inhibition of renal glucose reabsorption [16], SGLT2 inhibitors exert wide-ranging metabolic benefits that extend to the liver [17,18], heart [19,20], and kidney [21]. Clinical and preclinical studies have consistently demonstrated improvements in hepatic steatosis [22-24], inflammation [25], and fibrosis [26] following SGLT2 inhibition, which cannot be solely explained by glucose lowering.

Mechanistically, SGLT2 inhibitors reprogram the whole-body energy metabolism by reducing insulin resistance [27,28], alleviating lipotoxicity [29,30], restoring mitochondrial function [31], and modulating intracellular Ca²⁺ homeostasis [32-34]. These systemic actions improve hepatic metabolic balance and suppress inflammatory and fibrotic pathways central to liver disease progression. Thus, SGLT2 inhibitors have emerged as promising candidates for the treatment of MASLD and related metabolic disorders, offering a new paradigm for liver protection through metabolic remodeling rather than by direct hepatocellular targeting (Fig. 1).

EVOLUTION OF SELECTIVE SGLT2 INHIBITORS

In the kidney, SGLT2 is responsible for bulk glucose reabsorption in the early segment of the proximal convoluted tubule, whereas SGLT1 reabsorbs the remaining glucose in the later segment. Together, they form a highly efficient system that prevents urinary glucose loss under normal physiological conditions [21]. In the intestine, SGLT1 mediates postprandial glucose uptake across the apical membrane of enterocytes, supplying metabolic substrates essential for intestinal energy homeostasis (Fig. 2A). Loss-of-function mutations in SGLT1 lead to glucose-galactose malabsorption [35], causing severe osmotic diarrhea and dehydration in neonates. In contrast, loss-of-function mutations in SGLT2 result in familial renal glucosuria [36,37], which is characterized by persistent urinary glucose excretion without hyperglycemia or systemic metabolic abnormalities. Notably, SGLT2 inhibition promotes glucosuria and mild energy depletion, triggering a metabolic shift toward lipid oxidation and an enhanced metabolic flexibility, thereby improving insulin sensitivity and energy balance (Fig. 2B) [15].

The therapeutic development of SGLT2 inhibitors originates from phlorizin [38], a natural O-glycoside isolated from apple tree bark in the 19th century. Although phlorizin effectively induces glucosuria by inhibiting both SGLT1 (intestinal) and SGLT2 (renal) transporters; however, its poor oral bioavailability and nonselective inhibition limited the clinical utility due to gastrointestinal side effects. Structural optimization led to the development of C-arylglucosides [39], in which the labile Oglycosidic bond was replaced by a stable C–C linkage, markedly improving metabolic stability and oral efficacy. This innovation led to the approval of dapagliflozin in 2012, followed by canagliflozin and empagliflozin [16], which achieved superior glycemic control and also demonstrated cardiorenal protective benefits.

All seven clinically approved agents (Fig. 2C), canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, and tofogliflozin, share a conserved C-arylglucoside scaffold [16,21], which enhances their stability compared to the natural prototype phlorizin. However, variations in aryl substitution, heteroatom bridging (O, S, or spiro configurations), and hydrophobic side chain tuning yield distinct SGLT2/SGLT1 selectivity profiles [40]. Among these, canagliflozin exhibits the lowest selectivity (~250-fold) owing to its fluorinated thiophenyl moiety, which enables partial SGLT1 inhibition and intestinal glucose absorption modulation. Dapagliflozin (~1,200-fold) contains a stable 4-chloro-3-[(4-ethoxybenzyl)phenyl]-C-glucoside structure that optimizes renal specificity through balanced polarity. Empagliflozin, the most selective inhibitor (~2,500-fold), incorporates a tetrahydrofuran bridge that stabilizes the aryl-glucose interaction, whereas ertugliflozin (~2,000-fold) features ethoxy-substituted chlorophenyl and cyclopropyl-oxy groups that improve potency and pharmacokinetic behavior. Ipragliflozin (~1,000-fold) has an early generation design with a methyl-substituted arylglucoside architecture, ensuring renal selectivity and faster hepatic clearance. Luseogliflozin (~1,600 to 1,700-fold) introduces a thio-C-arylglucoside modification that enhances lipophilicity and membrane affinity, whereas tofogliflozin (>1,800-fold) employs an O-spiroketal ring system that confers exceptional SGLT2 specificity and metabolic stability.

Mechanistically, differences in SGLT2 selectivity are correlated with distinct tissue actions and systemic effects. Highly selective agents, such as empagliflozin, tofogliflozin, and ertugliflozin, act predominantly in the kidney, promoting glucosuria and natriuresis while minimizing intestinal and hepatic glucose-handling interference. In contrast, partial SGLT1 inhibition by canagliflozin influences both renal and intestinal glucose flux, altering systemic glucose availability and hormonal feedback. These differential effects exemplify how the rational chemical optimization of the C-arylglucoside scaffold translates into diverse physiological actions and broadens its therapeutic versatility from glycemic regulation to cardiovascular and renal protection [14,15].

MECHANISTIC INSIGHTS OF SGLT2 INHIBITION

Improved insulin sensitivity and glucose homeostasis

SGLT2 inhibitors lower blood glucose levels, primarily by inhibiting renal glucose reabsorption, leading to reduced chronic hyperinsulinemia and improved systemic insulin sensitivity. In the liver, SGLT2 inhibition enhances insulin receptor and protein kinase B (Akt) phosphorylation in diabetic models [41], thereby restoring insulin-mediated suppression of gluconeogenesis. Interestingly, transient inhibition following a single dose of SGLT2 inhibitor in lean mice suppresses hepatic Akt/glycogen synthase kinase 3β (GSK3β) signaling and promotes gluconeogenic gene expression (glucose-6-phosphatase, catalytic subunit [G6pc], phosphoenolpyruvate carboxykinase 1 [Pck1]) [42]. However, chronic treatment of obese insulin-resistant mice reverses these defects, normalizing Akt activation and suppressing pathological hepatic glucose output (Fig. 3A) [28].

In addition to insulin signaling, SGLT2 inhibitors activate hepatic adenosine monophosphate-activated protein kinase (AMPK) through glucosuria-induced energy stress, increasing the adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio, and recruiting liver kinase B1 (LKB1) to phosphorylate AMPK at Thr172 [43]. Activated AMPK promotes β-oxidation and inhibits lipogenesis by inactivating acetyl-CoA carboxylase 1/2 (ACC1/2) and sterol regulatory element-binding protein 1c (SREBP1c), collectively driving a metabolic shift, from anabolic to catabolic programs. Consistent with this, studies have reported that ipragliflozin alleviates high-fat diet–induced steatosis through AMPK–sirtuin 1 (SIRT1) activation [44], enhancing thermogenic gene expression and lipid oxidation independently of glucose lowering, suggesting direct metabolic reprogramming. Further evidence by Lee et al. [17] showed that dapagliflozin activates AMPK–SIRT1 signaling and autophagy, enhancing phosphoenolpyruvate carboxykinase (PEPCK) and microtubule-associated protein 1A/1B-light chain 3B-II (LC3B-II) expression while suppressing ACC and fatty acid synthase (FAS). This remodeling promotes carnitine palmitoyltransferase 1α (CPT1α)-mediated fatty acid oxidation and lipid clearance, alleviating steatosis independent of systemic lipid changes. Similarly, Yang et al. [45] demonstrated that dapagliflozin exerts dual metabolic actions—enhancing hepatic energy mobilization via AMPK–SIRT1– peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) signaling and reducing lipotoxic and ER stress-related injury. Collectively, SGLT2 inhibitors exert multifaceted hepatoprotective effects by restoring insulin/Akt signaling, activating AMPK–SIRT1–autophagy pathways, and reprogramming lipid and glucose metabolism (Fig. 3A). These actions suppress excessive gluconeogenesis and also enhance fatty acid oxidation and stress resilience, establishing SGLT2 inhibition as a systemic metabolic modulator besides achieving glycemic control.

Reduction of lipotoxicity and steatosis

Improved mitochondrial function is an important downstream consequence of the metabolic reprogramming triggered by SGLT2 inhibition. By stimulating fatty acid β-oxidation, SGLT2 inhibitors increase substrate flux into the mitochondria, promoting mitochondrial biogenesis, and expanding oxidative capacity. For instance, empagliflozin treatment markedly upregulates PGC-1α and uncoupling protein 2 (UCP2), which is consistent with activation of mitochondrial adaptive pathways; however, direct evidence of enhanced mitochondrial respiration or thermogenic activity was not demonstrated [41]. This adaptive response enables hepatocytes to metabolize excess fatty acids more efficiently, preventing the accumulation of cytotoxic lipid intermediates. Enhanced mitochondrial function contributes to reduced oxidative stress because improved electron transport chain efficiency minimizes ROS leakage. In steatotic livers, mitochondrial overload and lipid oxidation activate ROS-producing oxidases, driving lipid peroxidation and inflammation. SGLT2 inhibitors counteract this process not only by alleviating substrate surplus but also by exerting direct antioxidant effects, thus breaking the link between lipotoxicity and inflammation (Fig. 3A).

In addition to their mitochondrial effects, SGLT2 inhibitors modulate ER stress responses, which are closely linked to lipid and Ca²⁺ homeostasis. In both experimental and clinical settings, SGLT2 inhibition reduces the hepatic markers of oxidative and ER stress [46,47]. In obese mouse models, dapagliflozin downregulated inositol-requiring enzyme 1α (IRE1α) and C/EBP homologous protein (CHOP) while restoring autophagy, thereby mitigating proteotoxic stress and preserving hepatocyte viability [48]. Emerging evidence suggests that SGLT2 inhibitors coordinate mitochondrial and ER homeostasis to protect hepatocytes from metabolic stress [32]. They preserve ATP production, stabilize the mitochondrial membrane potential, and improve oxidative phosphorylation, collectively preventing apoptosis. Concurrently, they modulate the IRE1α, PERK, and activating transcription factor 6 (ATF6) branches of the unfolded protein response (UPR), which enhances proteostasis, Ca²⁺ handling, and autophagic flux. By rejuvenating mitochondrial metabolism and curbing ROS generation, SGLT2 inhibitors disrupt the pathological feedback loop linkages to oxidative stress, ER dysfunction, and cellular injury (Fig. 3A). These actions not only attenuate steatosis and inflammation in the liver but also confer cardioprotective benefits by restoring mitochondrial–ER coupling in cardiac tissue. Collectively, these multifaceted effects underscore the potential of SGLT2 inhibitors as metabolic reprogramming agents capable of reversing organ-level injuries in both MASLD and diabetic cardiomyopathy.

Anti-inflammatory and antifibrotic effects

Chronic inflammation represents a central pathogenic driver of MASH progression toward fibrosis, linking metabolic stress to the structural remodeling of the liver. SGLT2 inhibitors have consistently demonstrated hepatoprotective and anti-inflammatory effects, largely secondary to improvements in glucose and lipid metabolism, which mitigate lipotoxic and oxidative stress [24,49]. Experimental and clinical data reveal marked reductions in hepatic expression of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin 1β (IL-1β), accompanied by decreased infiltration of inflammatory macrophages [22,41,50]. Concomitantly, SGLT2 blockade promotes an anti-inflammatory shift characterized by the upregulation of IL-10 and polarization toward M2 macrophages, which facilitate tissue repair and inflammation resolution (Fig. 3B). These immunomodulatory effects correspond to the suppression of nuclear factor kappa B (NF-κB) activity and inhibition of inflammasome components, indicating a broad attenuation of inflammatory signaling cascades.

In parallel, SGLT2 inhibitors exert direct antifibrotic effects limiting the activation and proliferation of hepatic stellate cells, which are the principal effectors of collagen synthesis and scar formation [22,24,49,50]. Key profibrogenic pathways, particularly transforming growth factor-β (TGF-β)/Smad signaling, are downregulated following SGLT2 inhibition, resulting in reduced transcription of TGF-β, collagen type I alpha 1 chain (COL1A1), and collagen type III alpha 1 chain (COL3A1), as well as a lower hepatic collagen deposition in diabetic and MASH models [22,51-54]. Moreover, inhibition of inflammatory cytokines, such as IL-17, further prevents the perpetuation of fibrogenic loops. Several studies have also reported reduced expression of tissue inhibitors of metalloproteinases and a relative increase in matrix metalloproteinases, shifting the balance toward extracellular matrix degradation (Fig. 3C) [55]. Through the dual suppression of inflammation and fibrogenesis, SGLT2 inhibitors intercept the two major pathogenic axes of steatohepatitis, cellular injury, and fibrotic remodeling, ultimately preserving hepatic structure and metabolic function.

Restoration of intracellular Ca²⁺ homeostasis

Beyond their well-established metabolic actions, SGLT2 inhibitors appear to modulate intracellular ion dynamics, particularly the regulation of Ca²⁺ homeostasis within the ER. Under metabolic stress conditions, hepatocytes commonly exhibit ER Ca²⁺ depletion accompanied by cytosolic Ca²⁺ overload, leading to ER stress, impaired protein folding, and activation of cell death pathways [9,56]. Although direct hepatocyte-specific evidence is still limited, emerging data from other metabolic tissues suggest that SGLT2 inhibition may enhance sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) activity and support ER Ca²⁺ reuptake, and this concept should be regarded as a hypothetical mechanism that requires future confirmation in liver cells [9].

Intracellular Ca²⁺ acts as a negative regulator of insulin signaling by forming complexes with phosphorylated phosphoinositides (PIP) such as PI(3,4,5)P₃. These Ca²⁺–PIP complexes disrupt the electrostatic binding between PH domain-containing proteins (AKT, PLCδ, insulin receptor substrate 1 [IRS1]) and membrane PIPs [57], thereby blocking their membrane translocation and impairing downstream insulin signaling. Molecular dynamics simulations and biochemical studies confirm that this mechanism reflects a direct ionic coordination between Ca²⁺ and adjacent phosphate groups in PIPs [58]. In obesity and palmitate-induced lipotoxicity, Ca²⁺ overload exacerbates this inhibition, whereas drugs, such as candesartan, alleviate insulin resistance by suppressing Ca²⁺ overload and restoring AKT membrane localization and SERCA2 expression in the liver [59]. Accordingly, the restoration of intracellular Ca²⁺ homeostasis by SGLT2 inhibitors should be interpreted as a proposed working model that may contribute to improved insulin signaling, with further hepatocyte-specific studies required to validate this mechanism (Fig. 3D).

Studies on cardiac myocytes and fibroblasts demonstrate that empagliflozin augments SERCA2 function, facilitating Ca²⁺ reuptake into the ER, shortening cytosolic Ca²⁺ transients, while preventing Ca²⁺ overload [60]. This effect is thought to occur, in part, through Na⁺/H⁺ exchanger inhibition, which lowers intracellular sodium and corrects alkalosis, secondarily improving Ca²⁺ extrusion via the Na⁺/Ca²⁺ exchanger. In hepatocytes, similar normalization of Ca²⁺ cycling is likely to mitigate ER stress, enhance protein folding, and attenuate the UPR [9], a major pathogenic feature of MASH. Stabilization of Ca²⁺-dependent signaling pathways, such as inositol trisphosphate (IP₃)-mediated signaling, could further support metabolic processes, including glycogen synthesis and lipid oxidation. Complementary evidence from cardiac ischemia/reperfusion injury (IRI) models reinforces the protective role of SGLT2 inhibitors in SERCA2 preservation [61]. Specifically, dapagliflozin prevents xanthine oxidase (XO)-mediated oxidative modification and SERCA2 inactivation, thereby maintaining efficient Ca²⁺ sequestration in the ER and stabilizing cytosolic Ca²⁺ homeostasis. Thus, dapagliflozin suppresses Ca²⁺/calmodulin-dependent kinase II (CaMKII) activation and cofilin phosphorylation, which protects against F-actin depolymerization, cytoskeletal collapse, and endothelial apoptosis. In ischemic microvessels, this mechanism preserves the endothelial barrier integrity and perfusion, effectively reducing IRI-induced cardiac microvascular damage. Taken together, these findings reveal a unifying mechanistic framework in which SGLT2 inhibitors fortify the SERCA2-dependent Ca²⁺ handling system, curbing both oxidative and ER stress in hepatic and cardiac tissues. By preventing Ca²⁺ dysregulation and maintaining ER-mitochondrial crosstalk, these drugs reinforce cellular homeostasis, providing a mechanistic basis for their observed benefits in metabolic syndrome, MASH, and ischemic heart disease [60].

CLINICAL EVIDENCE OF HEPATIC BENEFITS

Accumulating clinical and translational evidence indicates that SGLT2 inhibitors provide significant hepatic benefits to patients with MASLD [4,62,63], regarding both individuals with and without T2DM. Across multiple randomized controlled trials and real-world studies, treatment with SGLT2 inhibitors has been shown to improve biochemical, imaging, and histological markers of liver health, reflecting a broad and consistent hepatoprotective effect (Table 1). Consistent with these findings, multiple randomized and meta-analytic studies have demonstrated that SGLT2 inhibitors, particularly empagliflozin [64] and dapagliflozin [65], significantly reduce hepatic steatosis and improve fibrosis in patients with MASLD. In addition, meta-analyses of mixed SGLT2 inhibitor trials [66] further confirmed class-wide efficacy in reducing the hepatic fat fraction and improving noninvasive fibrosis indices across diverse metabolic populations. Similarly improvements have been reported for ipragliflozin [67] and canagliflozin [68], supporting the broader hepatoprotective potential of this drug class.

Biochemically, SGLT2 inhibitor therapy leads to a significant reduction in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, which are typically elevated in patients with hepatic steatosis and inflammation. These reductions correlate with hepatic fat accumulation and inflammation attenuation, suggesting a true disease-modifying effect rather than a mere metabolic artifact. A meta-analysis of clinical trials reported an approximately 20% reduction in liver fat content, measured by magnetic resonance imaging (MRI)-proton density fat fraction (PDFF), and a marked improvement in ALT levels [64,69]. In a 24-week trial of empagliflozin in patients with diabetic MASLD, ALT levels decreased by nearly 20%, in parallel with a 13% relative reduction in MRI-measured liver fat [70]. Other biochemical parameters, such as γ-glutamyl transferase (γ-GTP) and plasma ferritin, also improved with treatment, reflecting a reduction in hepatic oxidative stress and systemic inflammation. From an imaging perspective, quantitative modalities such as MRI-PDFF and FibroScan-controlled attenuation parameter (CAP) have consistently shown decreases in hepatic fat fraction following SGLT2 inhibitor therapy. For instance, in one study of patients with T2DM and MASLD, 6 months of empagliflozin treatment reduced the liver fat fraction from ~15% to ~13%, whereas untreated controls showed progressive fat accumulation [64,70]. Similarly, dapagliflozin therapy reduced hepatic fat by 20% to 30% relative to baseline, as assessed by MRI-PDFF [69]. Network meta-analyses comparing antidiabetic agents have ranked SGLT2 inhibitors among the most effective classes for reducing hepatic fat, with efficacy comparable to or slightly lower than that of glucagon-like peptide-1 (GLP-1) receptor agonists [71]. Notably, empagliflozin achieved the highest efficacy ranking for MRI-measured fat reduction in one comparative analysis, even surpassing thiazolidinedione pioglitazone, considered the gold standard for MASH management [71]. Although limited, histological data are encouraging. Several small biopsy-based studies have demonstrated improvements in the NAFLD Activity Score, particularly in steatosis and hepatocyte ballooning, following SGLT2 inhibitor therapy [72]. Early evidence also indicates a potential hepatic fibrosis regression, with some trials noting a modest reduction in liver stiffness on FibroScan following SGLT2 inhibition. These findings align with the biochemical and imaging trends, collectively suggesting that SGLT2 inhibitors may act on both metabolic parameters and underlying hepatic pathology.

While most available data come from diabetic populations, emerging studies in nondiabetic MAFLD revealed that the beneficial effects of SGLT2 inhibitors extend beyond glycemic control. A randomized controlled trial of empagliflozin in nondiabetic MAFLD demonstrated significant reductions in both liver fat and fibrosis despite normal fasting glucose levels [46]. In that 24-week study, although CAP did not significantly change across the entire cohort, patients with more severe baseline steatosis (CAP ≥302 dB/m) experienced a substantial steatosis reduction, with 37% of empagliflozin-treated patients showing improvement compared to 17% in the placebo group [46]. Importantly, liver stiffness decreased significantly from 6.0 to 5.3 kPa (P=0.001) in the empagliflozin group, whereas it remained unchanged in the placebo-treated subjects [46]. These changes were accompanied by significant reductions in ALT, AST, and fasting insulin levels, supporting an overall improvement in hepatic insulin sensitivity and metabolic regulation. GLP-1 receptor agonists (e.g., liraglutide and semaglutide) have shown impressive efficacy in inducing weight loss and resolving MASH histology. However, SGLT2 inhibitors appear nearly equivalent in their ability to reduce liver fat despite inducing less weight loss [71]. Furthermore, SGLT2 inhibitors confer broad cardiometabolic protection, including renal and heart failure benefits, which enhances their therapeutic value in patients with MASLD, who often have overlapping cardiovascular risk factors. Compared to pioglitazone, SGLT2 inhibitors offer similar or greater hepatic metabolic improvements while causing fewer adverse effects, such as weight gain and fluid retention. Supporting this, a large real-world study in Japan found that patients receiving SGLT2 inhibitors had a significantly lower risk of hepatic decompensation events than those receiving pioglitazone, despite achieving similar glycemic control [73]. Importantly, emerging observational real-world cohort data suggest that SGLT2 inhibitor therapy may be associated with lower long-term risks of fibrosis progression and advanced liver outcomes, including cirrhosis, hepatic decompensation, and hepatocellular carcinoma, although these findings remain hypothesis- generating and require confirmation in prospective trials [72]. Although definitive histological endpoints from large MASH trials are still awaited, these observations indicate a potential for SGLT2 inhibitors to influence the long-term trajectory of MASLD. Thus, SGLT2 inhibitors improve liver enzyme profiles, reduce hepatic steatosis, as assessed by imaging, and potentially slow fibrosis progression in both diabetic and nondiabetic populations. Their hepatic benefits appear to stem from enhanced insulin sensitivity, improved mitochondrial and ER functions, and reduced lipotoxicity and oxidative stress, which collectively restore hepatocellular metabolic homeostasis. As large-scale trials continue to elucidate their histological efficacy, SGLT2 inhibitors represent a promising and versatile therapeutic class for MASLD management, offering metabolic, hepatic, and cardioprotective advantages that make them a cornerstone in the evolving treatment landscape.

THERAPEUTIC IMPLICATIONS AND FUTURE DIRECTIONS

SGLT2 inhibitors represent a promising therapeutic option for the early management of MASLD, particularly in patients with simple steatosis or mild MASH, where improving insulin resistance and reducing hepatic fat may help halt disease progression. Given the high prevalence of undiagnosed MAFLD among individuals with T2DM, early screening and initiation of SGLT2 inhibitor therapy are increasingly advocated [4,15,74]. Both the American Association of Clinical Endocrinology and Japanese MASH guidelines now recommend SGLT2 inhibitors as adjunct therapy in diabetic patients with MAFLD [75,76]. By improving glycemic control and promoting modest weight loss, these agents target the two key drivers of MASLD and is an attractive pharmacological complement to lifestyle modifications. Combination therapy offers an additional avenue for optimizing outcomes. Co-administration of GLP-1 receptor agonists or pioglitazone may yield additive or synergistic effects through distinct yet complementary mechanisms, such as enhanced insulin sensitivity, reduced lipogenesis, and improved cardiorenal function. Early data indicated greater reductions in liver fat and transaminases when empagliflozin was combined with GLP-1 therapy [18,72], and preclinical models showed additive protection when paired with dipeptidyl peptidase 4 (DPP-4) inhibitors [72]. Because MASLD involves multiple interconnected metabolic pathways, experts have emphasized the need for multi-target therapeutic trials [4]. Owing to their broad metabolic benefits and cardiovascular protection, SGLT2 inhibitors are well positioned as core agents in combination regimens [15,16,21,77].

From a safety perspective, SGLT2 inhibitors have demonstrated a favorable profile in patients with metabolic liver disease [72]. They rarely induce hypoglycemia and most adverse effects, such as genital infections or mild diuresis, are manageable. In compensated cirrhosis, these drugs appear to be safe and may even lower the risk of hepatic decompensation [73]. Monitoring the hydration status and renal function remains essential, as efficacy diminishes with severe renal impairment. Rare cases of euglycemic ketoacidosis underscore the need for patient education on ‘sick day precautions’ [78]. Overall, the benefit–risk balance favors SGLT2 inhibitors given their metabolic, hepatic, and cardioprotective effects [79-81].

Clinically, SGLT2 inhibitors are now endorsed by major endocrinology and diabetes societies for patients with coexisting MAFLD and diabetes [4,15,21,28,70]. Hepatology guidelines are beginning to reflect this metabolic approach. For diabetic or obese individuals with MASLD, SGLT2 inhibitors provide a rational therapeutic choice to improve glycemic, hepatic, and systemic outcomes. For nondiabetic MASLD, lifestyle modification remains the first-line treatment; however, ongoing clinical trials is needed to clarify its potential standalone or adjunctive use. As research advances, SGLT2 inhibitors are likely to become integral to comprehensive metabolic liver disease management, providing multiorgan protection through systemic metabolic reprogramming. However, the precise molecular mechanisms by which SGLT2 inhibitors directly improve hepatic function remain unclear. Future studies are needed to clarify how these agents modulate hepatocellular metabolism, Ca²⁺ homeostasis, and mitochondrial function, to establish the mechanistic links between metabolic remodeling and liver-specific protection (Fig. 4).

CONCLUSIONS

SGLT2 inhibitors have redefined the therapeutic landscape of metabolic liver disease by acting as systemic metabolic regulators rather than as organ-specific agents. Their coordinated actions on glucose, lipid, and Ca²⁺ homeostasis restore hepatocellular resilience against metabolic stress [4,15,16,21]. Mechanistically, they suppress hepatic gluconeogenesis [17,41,42] and de novo lipogenesis [28], enhance mitochondrial biogenesis and redox balance [32,45], attenuate inflammatory [20,82] and fibrotic signaling [4], and normalize intracellular Ca²⁺ dynamics via SERCA2 activation [61]. These interlinked pathways converge to durably improve hepatic structure and function.

Functionally, SGLT2 inhibitors bridge the gap between metabolic and hepatocellular therapeutics by targeting shared molecular nodes that govern energy balance, oxidative stress, and Ca²⁺ signaling. Their ability to restore the SERCA-dependent ER-mitochondrial interface distinguishes them from other metabolic agents. By promoting renal glucose excretion, these agents induce a mild energy deficit that enhances lipid oxidation and insulin sensitivity, thereby alleviating hepatic steatosis [31,44,50]. Concurrently, the restoration of Ca²⁺ and phosphoinositide homeostasis strengthens ER-mitochondrial coupling, reinforcing metabolic efficiency and survival signaling across the kidney–liver–metabolic axis [9,33,56,60]. This integrative model highlights SGLT2 inhibitors as prototype therapeutics linking renal energy regulation to hepatic homeostasis via the Ca²⁺–PIP–SERCA regulatory axis, offering a unifying mechanism for treating MASLD and related metabolic disorders.

From a translational perspective, SGLT2 inhibitors represent a paradigm shift in the management of MASLD. Their demonstrated efficacy in reducing hepatic fat, improving liver enzyme profiles, and attenuating fibrosis, while conferring cardiovascular and renal protection, supports their inclusion in multisystem metabolic treatment frameworks [4,21,80]. Notably, targeting Ca²⁺–SERCA signaling introduces a mechanistically novel dimension that complements established metabolic regulators, such as AMPK, PPARα, and SIRT1. By re-establishing Ca²⁺-integrated metabolic equilibrium, SGLT2 inhibitors pave the way for next-generation hepatometabolic therapies designed to treat the root causes of fatty liver disease rather than its downstream sequelae.

Future research should elucidate the precise intracellular mechanisms by which SGLT2 inhibitors improve hepatic function, particularly their influence on SERCA activity, PIP-dependent Akt signaling, and ER-mitochondrial communication. Integrating metabolomic, phosphoproteomic, and Ca²⁺-imaging biomarkers into clinical trials will help identify patient subsets that are most responsive to therapy and refine precision medicine strategies. Ultimately, this mechanistic understanding may guide the rational development of SGLT2-derived analogs, thereby advancing the therapeutic frontier for MASLD and other metabolic liver diseases.

Article information

CONFLICTS OF INTEREST

Byung-Chul Oh is a deputy editor of the journal. But he was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

ACKNOWLEDGMENTS

This study was funded by the National Research Foundation of Korea, funded by the Korean government (MSIT) (NRF-2021R1A5A2030333 and 2022R1A2C2092700), and the Gachon University Research Fund (GCU-202406080001).

Fig. 1.

Renal sodium-glucose cotransporter 2 (SGLT2) inhibition drives systemic metabolic reprogramming and hepatoprotection in metabolic dysfunction-associated steatotic liver disease (MASLD). This schematic illustrates how SGLT2 inhibition in the renal proximal tubule initiates a systemic metabolic shift that benefits the diseased liver in MASLD. By blocking glucose reabsorption via SGLT2, these agents promote urinary glucose excretion and reduce circulating glucose levels, creating a fasting-like metabolic environment. This systemic reprogramming leads to improved hepatic mitochondrial–endoplasmic reticulum (ER) homeostasis, suppression of inflammatory and fibrogenic pathways, and restoration of intracellular Ca²⁺ balance. Through these coordinated mechanisms, SGLT2 inhibitors exert anti-steatotic, antiinflammatory, antifibrotic, and anti-apoptotic effects that collectively promote hepatic recovery and maintain liver health. GLUT2, glucose transporter 2; MASH, metabolic dysfunction-associated steatohepatitis.

Fig. 2.

Tissue-specific functions of sodium-glucose cotransporter 1 (SGLT1) and sodium-glucose cotransporter 2 (SGLT2) in glucose handling and structural development of modern SGLT2 inhibitors. (A) Diagram of intestinal glucose absorption mediated by SGLT1. In the small intestine, SGLT1 on the apical membrane of enterocytes co-transports glucose with sodium ions (2 Na⁺:1 glucose), enabling efficient uptake of dietary glucose into epithelial cells and subsequent release into the bloodstream via basolateral glucose transporter 2 (GLUT2). (B) Renal glucose reabsorption in the nephron. SGLT2 in the early proximal convoluted tubule reabsorbs most filtered glucose, whereas SGLT1 in the distal segment retrieves the remaining fraction to minimize urinary glucose loss. Pharmacological blockade of SGLT2 reduces glucose and sodium reabsorption, resulting in glucosuria and improved systemic glucose regulation. (C) Structural progression from the natural Oglycoside phlorizin to clinically approved C-arylglucoside SGLT2 inhibitors. The figure depicts phlorizin and seven therapeutic agents—canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, and tofogliflozin. Phlorizin’s discovery provided the foundational scaffold for drug development, while subsequent C-arylglucoside modifications conferred resistance to enzymatic hydrolysis and enhanced oral bioavailability. Differences in their aryl substituents and heteroatom linkages contribute to variations in SGLT2 selectivity, metabolic stability, and pharmacokinetic properties.

Fig. 3.

Systemic and hepatocellular mechanisms underlying the protective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in metabolic-associated steatotic liver disease (MASLD). SGLT2 inhibitors exert multifaceted hepatoprotective effects through integrated systemic and cellular mechanisms that restore metabolic and calcium homeostasis in MASLD. (A) In hepatocytes, SGLT2 inhibition induces glucosuria and systemic energy deficit, activating adenosine monophosphate (AMP)-activated protein kinase (AMPK)–sirtuin 1 (SIRT1) pathways that suppress gluconeogenesis and lipogenesis while enhancing β-oxidation, mitochondrial respiration, and autophagic clearance. These effects alleviate proteotoxic and lipotoxic stress, contributing to mitochondrial–endoplasmic reticulum (ER) homeostasis. (B) In Kupffer cells, SGLT2 inhibitors attenuate nuclear factor kappa B (NF-κB) activation and inflammasome signaling, promoting a phenotypic switch from pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages that secrete interleukin 10 (IL-10), thereby suppressing hepatic inflammation. (C) In hepatic stellate cells, reduced transforming growth factor-β (TGF-β)/Smad signaling and downregulation of collagen genes (collagen type I alpha 1 chain [COL1A1], collagen type III alpha 1 chain [COL3A1]) mitigate fibrogenesis and extracellular matrix accumulation. (D) SGLT2 inhibitors may restore sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) function and intracellular Ca²⁺ homeostasis, as a proposed working model based on emerging but still limited hepatocyte-specific evidence. This conceptual mechanism suggests potential relief of ER stress and facilitation of protein kinase B (AKT) membrane localization, thereby improving insulin signaling, although additional studies are required to validate these pathways in liver cells. Collectively, these actions encompass metabolic reprogramming, mitochondrial–ER stabilization, anti-inflammatory and antifibrotic effects, and restoration of intracellular Ca²⁺ balance. PIP, phosphoinositides; IRS, insulin receptor substrate; PI3K, phosphatidylinositol 3-kinase; ATP, adenosine triphosphate; MASH, metabolic dysfunction-associated steatohepatitis; CPT, carnitine palmitoyltransferase; ACC, acetyl-CoA carboxylase; SREBP1c, sterol regulatory element-binding protein 1c; LC3B-II, light chain 3B-II; ETC, electron transport chain; IRE1α, inositol-requiring enzyme 1α; CHOP, C/EBP homologous protein; UPR, unfolded protein response; FAS, fatty acid synthase; PGC-1α, peroxisome proliferator-activated receptor γ coactivator-1α; ROS, reactive oxygen species.

Fig. 4.

Multisystem benefits, clinical applications, and future directions of sodium-glucose cotransporter 2 (SGLT2) inhibitors in metabolic dysfunction-associated steatotic liver disease (MASLD). This figure summarizes the broad therapeutic actions of SGLT2 inhibitors across multiple organ systems relevant to MASLD. Through a comprehensive metabolic intervention, SGLT2 inhibitors confer glycemic improvement and reduced insulin resistance (metabolic protection), attenuate hepatic steatosis, inflammation, and fibrosis (hepatoprotection), and ameliorate renal failure and fibrotic progression (renal protection). Additionally, they provide cardiovascular benefits, including reduced heart failure risk, improved diabetic cardiomyopathy, and enhanced vascular endothelial function. SGLT2 inhibitors can be used as monotherapy—improving hepatic fat burden and metabolic status—or in combination with glucagon-like peptide-1 (GLP-1) receptor agonists or pioglitazone for synergistic effects. Their safety profile is generally favorable, with attention to hydration status, renal monitoring, and rare occurrences of euglycemic ketoacidosis. Current clinical guidance supports the use of SGLT2 inhibitors as adjunct therapy in diabetic individuals with MASLD, while future studies are needed to clarify their long-term efficacy and their potential role in preventing progression to metabolic dysfunction-associated steatohepatitis. MAFLD, metabolic dysfunction-associated fatty liver disease.

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