Data summarized in Table S1 indicate that the prevalence of steatosis/NAFLD/MASLD [11–20] among adults with T2D ranges from 59% [19] to 87% [15]. These variations in the estimated prevalence may be explained by geographical/ethnic differences, T2D patient selection (primary care vs. referral clinics), study design (retrospective vs. prospective), as well as variable sensitivity of the tools used to diagnose MASLD [conventional ultrasonography, FibroScan, magnetic resonance imaging (MRI)]. Of concern, any type of liver fibrosis is found in 28% of cases [14, 20], and “at-risk MASH” (metabolic dysfunction-associated steatohepatitis)—defined as fibrosing liver disease with prominent signs of histological inflammatory activity—is found in 13.6% of cases, with cirrhosis identified in 6.8% of cases [13]. Collectively, these findings support the notion that early diagnosis of MASLD should be part of the holistic assessment among T2D patients [12, 18]. Certain predictors of progressively fibrosing liver disease may further guide the selection of subjects for more in-depth hepatological assessment for aggressive anti-fibrotic drug schedules [13]. These predictors include anthropometric indices suggesting severe (visceral and overall) obesity [12, 14, 18], female sex [20], low educational level [12], hypertransaminasemia [18], and hyperferritinaemia in non-hemochromatosis individuals [16].

Table S2 provides a more comprehensive assessment of the bidirectional association linking NAFLD/MASLD and T2D [21–29].

On one hand, pre-existing NAFLD exposes individuals to a doubled risk of incident T2D over a 5-year follow-up [21, 22]. The risk of incident T2D is also observed in the so-called “lean NAFLD” [26], suggesting that it is not caused by obesity but is rather mediated by the severity of NAFLD/MASLD [23, 26]. On the other hand, adults with T2D have a prevalence of MASLD ranging from 55.5% [24] to 59.67% [22], 65.04% [27], and 65.33% [28] in various studies. The risk appears to be higher in Europe than elsewhere [28], probably mirroring the variable methodology of European studies or a genuinely higher risk of T2D associated with European ethnicities or lifestyle habits.

In parallel with the development of NAFLD/MASLD, T2D also provides a biological milieu that facilitates the progression of liver disease. Accordingly, the global prevalence of NASH and advanced fibrosis among T2D subjects reportedly ranges from 37.3% and 17.0% [24], to 31.55% and 14.95% [27], to 40.78% and 15.49% [28], respectively. Collectively, these data reinforce a holistic approach aimed at triaging NAFLD/MASLD and fibrosing NASH/MASH among individuals with T2D. To this end, it may be important to consider that, in T2D patients, body mass index, age, male sex, the cut-off of vibration-controlled transient elastography and Asian ethnicity are associated with elevated liver stiffness, a surrogate, non-invasive biomarker of liver fibrosis [25].

MASLD, as a multisystem disorder, not only increases the risk of adverse liver outcomes but also has major extra-hepatic complications [30], such as cardiovascular disease (CVD), chronic kidney disease (CKD), and certain extra-hepatic cancers.

Compared to the extensive literature summarized in Table S2, studies assessing the prevalence of T2D among those with NAFLD are significantly limited in number, yet crucial for evaluating the global clinical and economic impact of T2D in patients with NAFLD or MAFLD.

In their meta-analysis of 395 published studies totalling 6,878,568 participants with NAFLD and 1,172,637 participants with MAFLD, Younossi et al. [31] reported that approximately 23% of patients with NAFLD also have T2D. Similarly, a more recent meta-analysis of 395 studies totalling 6,878,568 participants with NAFLD and 1,172,637 participants with MAFLD from 40 countries found that the pooled prevalence of T2D among NAFLD or MAFLD patients was 28.3% [95% confidence interval (CI) 25.2–31.6%] and 26.2% (95% CI 23.9–28.6%) globally [32].

Finally, a study involving 30,633 participants found that NAFLD increased the risk of pre-diabetes and T2D [33]. Conversely, pre-diabetes and T2D were also associated with an increased risk of NAFLD. In cross-lag path analysis, NAFLD was found to significantly affect the incidence of pre-diabetes (β = 0.285, p < 0.001), while the effect on T2D was not statistically significant. Additionally, pre-diabetes and T2D had a weak effect on the risk of NAFLD. In conclusion, this study demonstrates a bidirectional causal association between NAFLD and T2D through progression from NAFLD to pre-diabetes and then to T2D.

The pathways leading from MASLD to pre-diabetes and overt T2D involve the upregulation of hepatokines due to hypercaloric diets and hyperglycaemia, as well as peripheral and hepatic insulin resistance. Additionally, de novo lipogenesis is sustained by the liver being overwhelmed by hyperglycaemia and free fatty acids, leading to increased oxidative stress, inflammation, and fibrosis associated with intrahepatic oxidative phosphorylation [34]. These complex pathogenic connections explain why antidiabetic agents can reduce intrahepatic fat content [35] and effectively cure MASH in randomized controlled trials [34].

It is universally agreed that T2D significantly increases the risk of developing advanced fibrosis and cirrhosis in patients with MASLD, resulting from the combined effects of insulin resistance, inflammation, and lipotoxicity inherent in both conditions [38]. In a series of 501 individuals with T2D aged 50 years and older, showing a high prevalence of non-invasively assessed liver fibrosis and cirrhosis, Ajmera et al. [11] found that obesity and insulin treatment were associated with increased risks of advanced fibrosis (OR 2.50; 95% CI 1.38–4.54; p = 0.003 and OR 2.71; 95% CI 1.33–5.50; p = 0.006, respectively). In the same study, 2 out of 29 patients with cirrhosis were found to have hepatocellular carcinoma (HCC), and one subject had gallbladder adenocarcinoma [11]. This study clearly illustrates the severe outcomes of the interaction between MASLD and T2D, which also include a higher risk of liver-related mortality and the need for liver transplantation [39].

The pathomechanisms of MASLD-related hepatocarcinogenesis among those with T2D have been reviewed elsewhere [40, 41]. In short, they involve increased reactive oxygen species (ROS) production, endothelial damage, release of proinflammatory cytokines, and activation of the insulin-like growth factor (IGF) pathway. Additionally, sex and liver fibrosis play significant roles as modifiers for the risk of HCC compared to extra-hepatic cancers [42].

In addition to the increased risks of fibrosis, cirrhosis, primary liver cancer, and end-stage liver disease, MASLD has significant extra-hepatic implications [30], such as CVD, CKD, and certain extra‐hepatic cancers [43–45]. Emerging data suggest a progressively rising risk of CVD that is linked to the severity of MASLD. Incorporating liver-specific variables allows for improved risk stratification and targeted interventions to reduce the impact of CVD in this high-risk patient population [46]. In terms of CKD and end-stage renal disease, which are influenced by both T2D and MASLD [47], there appears to be a synergistic and deleterious interaction between these two conditions. In a national population-based retrospective cohort study, Park et al. [48], by analyzing 816,857 individuals over a median follow-up of 7.7 years, found that the presence of NAFLD was associated with a higher risk of adverse clinical outcomes in individuals with CKD.

The spectrum of extra-hepatic neoplasms associated with MASLD includes cancers of the (extra-hepatic) digestive system and urinary tract [45, 49]. Similarly, a meta-analysis of published observational studies assessing the associations between T2D and cancer incidence or mortality, with 151 cohorts globally totalling over 32 million people, 1.1 million cancer cases, and 150,000 cancer deaths [50] documented that T2D was associated with increased risk of nearly 100% for liver, pancreatic, and endometrial cancer, 86% for gallbladder cancer, 67% for kidney cancer, 64% for colon cancer, 62% for colorectal cancer, and less than 50% of other cancer incidences. Additionally, there was a 92% increased risk for pancreatic cancer mortality in individuals with T2D [50]. These findings support a causal association between T2D and liver, pancreatic, and endometrial cancer incidence, as well as pancreatic cancer mortality. The potential pathomechanism connecting MASLD, T2D, and the risks of extra-hepatic cancers has been previously discussed in this journal [51] and will not be reiterated here. The key points regarding the association between MASLD and T2D may be summarized as follows:

The prevalence of MASLD in T2D adults ranges from 59% to 87%.

PPARα, primarily expressed in organs with high oxidative capacity such as the liver, heart, and muscles, regulates fatty acid oxidation and energy expenditure [54]. By increasing the expression of genes involved in mitochondrial and peroxisomal β-oxidation, PPARα helps preserve the normality of lipid homeostasis. However, in the insulin-resistant state characteristic of T2D-related MASLD, lipid homeostasis can be overwhelmed by excessive free fatty acid influx and dysregulated by inflammatory signalling [55]. PPARβ/δ, which is widely distributed, supports fatty acid catabolism, insulin sensitivity, and mitochondrial function. However, its protective functions can be weakened in the presence of chronic systemic metabolic stress. PPARγ, initially identified as a factor induced during adipocyte differentiation, is mainly found in adipose tissue but is also present in the liver [56]. It plays a crucial role in adipocyte differentiation, lipid storage, and insulin sensitization. Nevertheless, in conditions closely related to T2D, such as adipocyte hypertrophy and inflammation, its activity may be disrupted, leading to a decreased ability to buffer lipids in adipose tissue and increased ectopic accumulation of intrahepatic lipids [56].

In T2D-related MASLD, insulin resistance in the adipose tissue leads to the release of free fatty acids into the bloodstream, overwhelming the liver’s capacity to oxidize them. Under physiological conditions, hepatic PPARα is activated to increase the expression of genes that facilitate β-oxidation, aiding in the efficient clearance of free fatty acids and thereby preventing the harmful build-up of triglycerides [57]. However, in individuals with T2D, hyperinsulinemia, coupled with hyperglycaemia and elevated levels of lipotoxic substrates, such as diacylglycerols and ceramides, can disrupt the normal function of PPARα. The persistently elevated levels of insulin stimulate the production of SREBP-1c, a potent factor that promotes steatogenesis if it is not balanced by PPARα-mediated fatty acid oxidation [58, 59]. Moreover, a pro-inflammatory environment, driven by cytokines like tumour necrosis factor-alpha (TNF-α) and interleukins released by dysfunctional adipose tissue, exacerbates liver damage by activating signalling cascades (e.g., JNK, IKK) that impair insulin signalling and harm hepatocytes. While PPARα possesses anti-inflammatory properties by inhibiting NF-κB and other inflammatory pathways, its effectiveness is compromised when its expression or activity is decreased by the metabolic dysfunctions inherent in T2D, leaving the liver vulnerable to ongoing lipotoxic stress [60].

PPARγ is a master regulator of adipocyte biology, orchestrating the formation of new adipocytes and the expression of enzymes essential for lipid storage and insulin sensitivity [61–63]. In physiological conditions, adipose tissue efficiently stores lipids to prevent their ectopic accumulation in the liver and muscles. However, in T2D, adipose tissue often becomes dysfunctional, leading to increased circulating free fatty acids, which cause steatosis and exacerbate hepatic insulin resistance. Moreover, dysfunctional adipose tissue releases higher levels of pro-inflammatory cytokines, which can hinder PPARγ activity, further worsening insulin resistance and affecting adipocyte differentiation [64]. Clinically, PPARγ agonists like thiazolidinediones (TZDs) have been studied for their ability to improve insulin sensitivity and reduce hepatic gluconeogenesis by enhancing the deposition of lipids in their physiological site, i.e., the adipose tissue, which contributes to reducing the ectopic lipid burden in the liver [65]. Nevertheless, these drugs can also have unwanted side effects such as weight gain, edema, and an increased risk of heart failure in certain patients, highlighting the delicate balance between the benefits and drawbacks of pharmacological PPAR modulation.

Although less extensively studied, PPARβ/δ is now recognized as a potentially influential modulator of energy balance and inflammation in T2D-related MASLD. PPARβ/δ is ubiquitously expressed in mammalian tissues and can promote fatty acid uptake and oxidation in both muscle and liver, thereby supporting systemic insulin sensitivity and metabolic flexibility [66]. Additionally, PPARβ/δ has demonstrated anti-inflammatory actions by inhibiting key inflammatory mediators, which may protect against obesity-related MASLD. However, disturbances in PPARβ/δ signalling, driven by chronic nutrient overload, insulin resistance, or interaction with other concurrent cofactors, can attenuate these favourable effects [66]. For mitochondria to effectively handle the increased load of lipid substrates in T2D, crosstalk with transcriptional co-activators such as PGC-1α is essential [67]. PPARβ/δ partners with PGC-1α to maintain mitochondrial biogenesis and lipid oxidation, but T2D-related epigenetic changes or co-activator dysfunction can undermine this adaptive mechanism, causing incomplete fatty acid oxidation and fuelling further lipotoxicity in the liver [67].

A key dimension of T2D-related MASLD is the interaction between lipid metabolism and inflammation, which Ertunc and Hotamisligil [68] have aptly termed “metaflammation”. In this process, PPARs act in conjunction with innate immune signalling pathways. The accumulation of lipotoxic lipid intermediates triggers endoplasmic reticulum stress responses and oxidative stress, activating JNK and IKK. These cellular responses to metabolic stress interfere with insulin receptor substrate phosphorylation, inhibiting downstream insulin signalling and promoting AP-1-mediated inflammatory gene expression [68]. This persistent sterile inflammation, along with other pro-fibrotic factors, contributes to the progression from simple steatosis to steatohepatitis, characterized by hepatocyte ballooning, mild lobular inflammatory changes, and potential development of chicken wire fibrosis. When PPAR isoforms are sufficiently active, their anti-inflammatory properties can help slow down this histological progression [69]. However, in T2D, epigenetic and post-translational modifications often reduce PPAR availability or ligand affinity, allowing chronic inflammation to progress in an uncontrolled manner.

Adipokines, hepatokines, and myokines secreted by adipose tissue, liver, or muscles, respectively, also directly impact hepatic PPAR function [70]. For example, adiponectin activates AMP-activated protein kinase (AMPK) and PPARα, serving as insulin sensitizers and promoting fatty acid oxidation while suppressing hepatic gluconeogenesis [70]. In T2D, reduced levels of adiponectin weaken PPARα signalling and exacerbate lipid accumulation in the liver. Meanwhile, leptin levels are elevated in obesity and T2D. Although leptin plays a crucial role in regulating appetite and energy expenditure, supranormal levels, indicating leptin resistance, can have negative effects. Hyper-leptinaemia can trigger hepatic fibrogenesis sustained by activated hepatic stellate cells through JAK/STAT and TGF-β pathways [71]. Therefore, the overall impact of adipose-derived signals on hepatic metabolism and inflammation often depends on a delicate balance of biochemical mediators and their interactions with PPARs.

Together, these factors underscore that T2D-related MASLD is not simply a disorder of hepatic lipid overload but rather a systemic disease of energy mismanagement, insulin resistance, and chronic inflammation, in which PPARs play a central coordinating role. Hyperinsulinemia and hyperglycaemia provoke transcriptional changes, such as increased SREBP-1c activity and decreased adiponectin signalling, which accelerate hepatic steatosis and inflammation. At the same time, PPARα’s ability to keep pace with fatty acid influx dwindles, PPARβ/δ struggles to maintain metabolic flexibility in muscle and liver, and the capacity of PPARγ to provide a safe lipid-storage reservoir in adipose tissue is constrained by inflammation and adipocyte dysfunction [72]. These processes culminate in a vicious circle that propagates T2D-related MASLD and elevates the risk of severe liver-related complications in a proportion of cases.

In exploring therapeutic approaches, researchers have evaluated various PPAR agonists to address the hepatic and systemic effects of T2D [73, 74]. Fibrates, which specifically activate PPARα, can slightly reduce hepatic steatosis by enhancing β-oxidation [73]. TZDs that target PPARγ are more effective at improving peripheral insulin sensitivity and may decrease liver fat, but their side effects limit widespread acceptance [75]. Dual PPARα/γ agonists, intended to enhance lipid metabolism and insulin action synergistically, faced safety concerns, leading to investigations on selective PPAR modulators (SPPARMs) that maximize benefits while minimizing adverse effects like weight gain and cardiovascular issues [76]. Recent studies have indicated that the naturally occurring flavonoid alpinetin shows promise as a therapeutic option for T2D treatment [77]. Additionally, PPARβ/δ agonists are being recognized for their insulin-sensitizing properties, but further evaluation is needed on their long-term safety and efficacy in hepatic disease [73]. Current advancements in medicinal chemistry, along with a growing understanding of PPAR interactions with co-activators, co-repressors, and epigenetic regulators, offer hope for more personalized interventions tailored to individual patient phenotypes.

Despite the notable role of pharmacotherapy, lifestyle interventions are paramount in the field of T2D-related MASLD. Weight loss, caloric restriction, reduction of excess carbohydrate consumption, and physical exercise can independently restore, at least partially, normal PPAR activity by correcting hyperinsulinemia, reducing inflammatory stress, and draining ectopic lipid pools [78]. Exercise particularly enhances muscle PPARα- and PPARβ/δ-driven lipid oxidation, reducing plasma free fatty acids that would otherwise exacerbate hepatic steatosis. Sustained caloric restriction can lead to a net improvement in adipose tissue health, supporting PPARγ function and lowering systemic inflammation [79]. These interventions, however, require patient engagement and long-term adherence, and are most advantageous if complemented by pharmacological agents that support or amplify PPAR-driven improvements in metabolic homeostasis.

Overall, the multifaceted roles of PPARs in the molecular pathogenesis of T2D-related MASLD illustrate how defects in nuclear receptor signalling, coupled with disruptions in insulin action, adipokine profiles, and inflammatory pathways, converge to drive liver disease progression. PPARα, PPARβ/δ, and PPARγ each contribute uniquely to hepatic lipid flux, adipose remodelling, and systemic insulin sensitivity, and their impairment under metabolic stress aggravates the cycle of lipotoxic injury and chronic inflammation characteristic of MASLD. As research has increasingly revealed epigenetic and post-translational layers of regulation, it has become clear that restoring PPAR function depends on a wide array of factors, including nutrient sensing, co-regulator availability, and inflammatory status [73, 78, 79]. These insights foster a more nuanced approach to therapy that exceeds simply activating or inhibiting a single PPAR isoform to addressing cofounding elements like SREBP-1c, NF-κB, or AMPK. Novel drug candidates strive to refine the therapeutic index by selectively targeting PPAR subsets in specific tissues or by combining PPAR modulation with other pathways, such as those acted upon by GLP-1 receptor agonists, SGLT2 inhibitors, or bile acid-related nuclear receptors like FXR, to achieve comprehensive metabolic control [80].

From a pathophysiological perspective, renaming NAFLD to MASLD reminds us that the development of steatosis and its progression to histologically more advanced stages of liver disease are driven by a constellation of metabolic derangements, of which PPAR dysfunction is a key component. In the pathogenic trajectory of T2D-related MASLD, the effects of PPARs on gene transcription, lipid partitioning, and inflammatory response extend far beyond the liver, heavily involving the adipose tissue, skeletal muscle, and immune cells [54, 81]. Therefore, it is vital to integrate an organ-spanning perspective in research and therapy development. The prospect of personalized medicine approaches, associating genetic and epigenetic markers of PPAR function to guide therapy choices, is appealing. Patients who exhibit robust responses to certain PPAR agonists may benefit significantly from such tailored approaches, whereas others may need combination regimens [82].

The systemic nature and complex pathogenesis of MASLD and MASH help to explain why oversimplified therapeutic approaches have yielded disappointing results [83]. In this context, the idea that different PPARs have varying activities on different cell and tissue targets helps to explain why Pan-PPAR agonists, such as Lanifibranor, can have pleiotropic actions and enhanced therapeutic potential in MASH and MASH-related hepatic and extra-hepatic morbidity [84]. Based on this conceptual background, the most important clinical trials with PPAR-agonists published in the MASLD arena are summarized in Table 1 [85–97].

Lin et al. [98] conducted a systematic review of relevant randomized double-blind controlled trials published until July 11, 2024. They found that for histologically proven fibrosis improvement, GLP-1-based poly-agonists were the most potentially effective, followed by FGF-21 analogues, THR-β agonists, Pan-PPAR agonists, and GLP-1R agonists. For MASH resolution in histology, GLP-1-based polyagonists were the most potentially effective, followed by THR-β agonists, GLP-1R agonists, FGF-21 analogues, and Pan-PPAR agonists.

The Pan-PPAR agonist Lanifibranor, at the highest dose, offers the chance to ameliorate hard liver histology outcomes among subjects with noncirrhotic NASH with a high grade of activity [93]. This implies that the activation of all three PPAR isotypes synergizes their therapeutic activity on multiple cell and target organs, thereby improving glucose and lipid metabolism and, simultaneously, also pro-inflammatory and pro-fibrogenic pathways [73, 99, 100].

Conversely, single PPAR agonists, such as various fibrates and glitazones, demonstrate strong anti-MASH activity in preclinical models. However, they only exhibit modest clinical efficacy on severe liver histology endpoints like MASH resolution and fibrosis regression [84]. Moreover, a clinically relevant and specific feature of PPAR agonists in the context of T2D-related MASLD is their positive impact on parameters of glucose and lipid metabolism in individuals with T2D [101]. Chatterjee et al. [101] observed this metabolic enhancement in their study of T2D patients treated with Saroglitazar, a novel dual PPARα and PPARγ agonist. After 14 weeks of treatment, participants experienced significant reductions in fasting and post-prandial plasma glucose, glycosylated haemoglobin, total cholesterol, low-density lipoprotein cholesterol, triglycerides, non-high-density lipoprotein cholesterol, and the ratio of triglyceride to high-density lipoprotein cholesterol. These improvements were observed without notable changes in body weight, blood pressure, high-density lipoprotein cholesterol, and serum creatinine. A concise overview of the isoform-specific dysfunctions, their clinical correlates, and the effects of corresponding agonists is provided in Table 2.

In summary, PPAR agonists like Pioglitazone and Lanifibranor offer potential benefits for MASLD and MASH, including improved liver health and insulin resistance. Pioglitazone can improve SLD and inflammation in MASH, especially when associated with T2D. It can reduce the NAFLD activity score (NAS) by 2 points and lead to MASH resolution without worsening fibrosis [102]. Saroglitazar usage decreases alanine aminotransferase (ALT) levels, liver fat content, insulin resistance, and dyslipidemia in MASLD patients [94]. Lanifibranor induces significant reductions in liver fat content in T2D patients with MASLD, while also improving hepatic and muscle insulin resistance and adipose tissue biology [103]. However, side effects and limitations exist, and careful patient selection and monitoring are crucial. While PPAR agonists show promise, more research is needed to optimize their use, identify the best candidates for treatment, and develop strategies to mitigate side effects [104]. In conclusion, the improved liver health associated with the usage of PPAR agonists may be envisaged as follows:

PPAR agonists can help reduce liver fat content, hepatic inflammation, and liver fibrosis in MASLD/MASH, potentially decreasing the risk of progression to more severe liver disease.

Moreover, as regards limitations and risks, it must be remembered that:

Pioglitazone must be used with caution in patients with pre-existing heart failure or other cardiovascular conditions, as it is linked to an increased risk of bone fractures and bladder cancer.

MicroRNAs (miRNAs) have gained prominence as approximately 22-nucleotide, non-coding regulators that fine-tune glucose handling, lipid turnover, inflammatory tone, and angiogenesis. Dysregulated miRNA profiles not only contribute to obesity, T2D, and CVD but also circulate stably in serum, making them attractive non-invasive biomarkers and therapeutic targets for the metabolic-syndrome continuum [105]. In addition to these post-transcriptional insights, a recent study showed that a methanolic leaf extract of Alpinia calcarata (A. calcarata) administered to high-fat-diet mice (200 mg/kg) significantly lowered body-weight gain, visceral-fat mass, total cholesterol, and triglycerides. The extract also down-regulated IL-6, COX-2, MCP-1, TNF-α, GLUT-4, and notably, PPARγ transcripts in adipose tissue, thereby attenuating adiposity and adipocyte inflammation [106]. Together, miRNA-based diagnostics and PPAR-targeting phytochemicals such as A. calcarata represent complementary, rapidly evolving strategies for intercepting the molecular drivers of metabolic syndrome and T2D-related MASLD.