Liver fibrosis, a pathological process characterized by excessive scarring within the liver due to persistent inflammation, remains a major clinical challenge. If unchecked, this fibrotic accumulation can escalate to cirrhosis, liver failure, or hepatocellular carcinoma. Although men generally exhibit a higher overall prevalence of liver fibrosis, the severity and rapid progression in women with underlying cardiometabolic comorbidities have become a focal concern. This study directly addresses this paradox, interrogating sex-specific biological and epidemiological differences underpinning liver fibrogenesis.

Lead author Jennifer Dodge, MPH, associate professor and researcher in medicine and population health sciences, emphasizes the clinical implications. “Our analysis confirms that women with high waist circumference and type 2 diabetes are at a disproportionately elevated risk for severe liver fibrosis compared to their male counterparts,” Dodge explains. “These findings underscore the urgent need for sex-tailored approaches in monitoring and managing cardiometabolic health to mitigate liver disease progression.”

Unlike many earlier investigations reliant on self-reported data or diagnostic coding, this study harnessed a robust dataset integrating laboratory biomarkers, anthropometric measurements, and advanced imaging techniques. The data were extracted from the CDC’s National Health and Nutrition Examination Survey (NHANES) spanning 2017 to 2020. This comprehensive dataset encompasses blood-based assays for cholesterol and glucose, clinical measurements of body mass index and waist circumference, and ultrasound-based evaluation of liver fibrosis and steatosis, enabling objective and precise phenotyping.

The cohort comprised nearly 6,000 adults representative of the U.S. population’s age, sex, race, and ethnicity. Researchers meticulously modeled the associations between liver fibrosis severity and key cardiometabolic factors: elevated waist circumference, hypertension, diabetes or prediabetes status, hypertriglyceridemia, and low HDL cholesterol levels. Importantly, analyses adjusted for confounders including age, smoking status, alcohol consumption, and demographic variables, thereby isolating sex-specific effects.

One of the study’s most striking revelations was the differential magnitude of fibrosis risk linked to elevated waist circumference. Women exhibited an 11-fold increase in liver fibrosis prevalence—from 0.8% in those with normal waist circumference to 9.2% among women with high waist circumference. Meanwhile, men experienced a comparatively smaller fourfold increase, rising from 4.4% to 17.0%. Similarly, the presence of type 2 diabetes or prediabetes resulted in a 2.8-fold surge in fibrosis risk in women, nearly double the relative risk observed in men (1.4-fold).

Even more compelling, the cumulative burden of multiple cardiometabolic derangements demonstrated an exponential relationship with fibrosis severity in women. Women harboring two or more cardiometabolic risk factors showed an 8.4-fold elevation in fibrosis prevalence, in stark contrast to a 2.6-fold increase in men. These findings collectively illuminate a critical vulnerability in women’s liver pathophysiology that may otherwise remain obscured by aggregate population statistics.

Experts hypothesize that hormonal influences, particularly estrogen, modulate hepatic fibrogenesis and contribute to sex-specific disease trajectories. Estrogen’s protective effects against liver injury and fibrosis are well documented; however, menopause-associated declines in estrogen may precipitate accelerated fibrosis progression in women. While this study did not directly examine menopausal status, it lays fertile groundwork for future investigations into the intersection of hormonal changes, cardiometabolic health, and liver disease outcomes.

Further research plans include longitudinal, prospective cohort studies to delineate causal pathways that underlie the observed sex disparities. Tracking individuals over time will allow for a more nuanced understanding of how cardiometabolic risk factors interact dynamically with liver fibrosis progression across the lifespan and between sexes. Additionally, the team aims to explore the impact of hormone replacement therapy on mitigating fibrosis risk among postmenopausal women.

Another priority is probing the relationship between sex, cardiometabolic dysfunction, and metabolic dysfunction–associated steatotic liver disease (MASLD), a non-alcoholic form of liver injury gaining global prevalence due to increasing obesity rates. Deciphering how sex and metabolic health interface in MASLD pathogenesis could revolutionize personalized medicine strategies to prevent liver-related morbidity and mortality.

This seminal study amplifies the call for clinicians to adopt a holistic mindset when managing cardiometabolic risk, recognizing that interventions to optimize glycemic control, lipid profiles, blood pressure, and body composition yield benefits extending beyond cardiovascular protection to encompass hepatic health. Tailored screening protocols attentive to sex-specific risk profiles could be key to early detection and improved outcomes in liver disease.

Liver fibrosis, long relegated as a secondary concern in metabolic syndrome management, now emerges as a central player intricately entwined with cardiometabolic pathways in a sex-dependent manner. This research not only advances our mechanistic understanding of fibrotic liver disease but also challenges existing paradigms, fostering a new era of precision hepatology rooted in gender medicine.

The collective expertise driving this study includes Somaya Albhaisi and Norah Terrault from the Gastrointestinal and Liver Diseases Division and Steve Kim from the Department of Population and Public Health Sciences, all affiliated with USC’s Keck School of Medicine. Supported by NIH funding, their collaborative endeavor underscores the critical intersection between epidemiology, clinical medicine, and basic science needed to tackle complex liver diseases confronting modern healthcare.

As liver fibrosis continues its stealthy climb as a public health menace, especially among women with diabetes and central obesity, these data call for urgent action. Holistic, informed strategies that leverage sex-specific insights harbor the promise of curbing the escalating global burden of liver disease—potentially saving countless lives through targeted prevention and therapeutic innovation.

Subject of Research: People

Article Title: Sex-Specific Cardiometabolic Profiles and Severity of Liver Fibrosis

News Publication Date: 9-Mar-2026

Web References: https://doi.org/10.1001/jamanetworkopen.2026.0863

Keywords: Liver, Liver damage, Fibrosis, Cardiovascular disorders, Metabolic disorders, Liver cancer, Cardiovascular disease, Type 2 diabetes

MASH describes an inflammatory liver disease triggered by metabolic dysregulation and fat accumulation within the liver. While MASLD incidence has surged globally in parallel with obesity and type 2 diabetes pandemics, the mechanistic details about why the disease progresses differently in males and females have remained elusive. This latest research reveals a distinctive role for GPR110, a G-protein-coupled receptor (GPCR) expressed selectively in hepatocytes, that differentially influences the disease course in male and female subjects.

The team employed hepatocyte-specific Gpr110 knockout mouse models to dissect the receptor’s role in MASH. Strikingly, female mice lacking Gpr110 in their liver cells exhibited marked protection against MASH. This sex-dependent protective effect was absent in male mice, suggesting an intrinsic biological divergence modulated by GPR110’s signaling. This discovery challenges the conventional one-size-fits-all approach to liver metabolic disease and calls attention to the importance of sex as a biological variable in future research and drug development.

Complementing their experimental model, the researchers analyzed genetic data identifying a variant of the GPR110 gene, known as rs937057 (a thymine to cytosine substitution), significantly associated with a higher prevalence of metabolic dysfunction-associated steatotic liver disease in women. This variant highlights a genetic predisposition component modulated through GPR110, pointing to the receptor’s potential as both a biomarker and a target for precision medicine in female populations.

Delving deeper into the molecular mechanisms, the investigation uncovered that the hepato-protective phenotype in female mice hinges on the presence and functional integrity of hepatic estrogen receptor alpha (Esr1). When Esr1 expression was knocked down in the liver, the protective benefits conferred by Gpr110 deletion were nullified. This indicates that GPR110 operates through modulating the estrogen receptor signaling axis, tightly linking metabolic dysfunction in the liver with hormonal regulation that differs between sexes.

At the biochemical level, the researchers demonstrated that GPR110 couples explicitly to the Gα_s protein subunit, which activates protein kinase A (PKA). This cascade leads to phosphorylation of the nuclear factor of activated T cells 2 (NFAT2), a transcription factor crucial in various cellular processes. Phosphorylated NFAT2 is hindered from translocating into the nucleus, thereby suppressing its capacity to drive Esr1 gene transcription in hepatocytes. Consequently, GPR110 activation results in a downregulation of estrogen receptor alpha signaling, diminishing the liver’s estrogen sensitivity and exacerbating MASH pathogenesis predominantly in females.

This elegant mechanistic insight not only clarifies GPR110’s role in hepatic metabolic regulation but also explains the observed sex differences in MASH progression. Women’s livers appear more sensitive to estrogen receptor signaling, which normally confers a protective effect. GPR110, by attenuating this pathway, inadvertently promotes disease development. The absence of this signaling in males suggests alternate pathogenic routes underlying their disease phenotype, further underscoring the complexity of metabolic liver disease.

The translational implications of these findings are profound. Therapeutic strategies aimed at inhibiting GPR110 function present a novel avenue for sex-specific intervention in MASH. Targeting this receptor selectively in hepatocytes could restore estrogen receptor alpha activity in women, thereby mitigating the progression of liver inflammation and fibrosis characteristic of MASH. Such approaches could revolutionize the currently limited treatment landscape for this increasingly prevalent disease.

Moreover, genetic screening for the rs937057 variant might allow identification of high-risk female individuals for early intervention and personalized treatment plans. Integration of genotype-guided therapy could enhance clinical outcomes and reduce the burden of advanced liver disease. The study also invites further research into whether modulation of GPR110 signaling can synergize with other therapeutic agents to amplify hepatoprotective effects.

Beyond its immediate clinical implications, this work sets a precedent for investigating other GPCRs in the liver and other metabolic organs. GPR110 exemplifies how sex hormones interact intricately with metabolic pathways, influencing disease susceptibility and progression. Investigating similar receptors and their downstream signaling networks can unveil additional molecular targets vital for combating metabolic disorders that display sex biases.

To ensure clinical relevance, future studies will need to explore GPR110’s role in human liver tissue and examine the receptor’s expression and function across diverse populations and metabolic conditions. Longitudinal studies could elucidate the receptor’s involvement in disease progression and response to lifestyle or pharmacological interventions. Additionally, the safety and efficacy of GPR110 antagonists in preclinical models must be rigorously evaluated before contemplating clinical trials.

In summary, this pivotal research elucidates the liver-specific G-protein-coupled receptor GPR110 as a key determinant of sex-specific differences in metabolic dysfunction-associated steatohepatitis. By selectively modulating hepatic estrogen receptor alpha signaling through a novel Gα_s–PKA–NFAT2 axis, GPR110 influences the susceptibility and severity of MASH primarily in females. These insights expand our understanding of the molecular underpinnings of liver metabolic diseases and pave the way for sex-specific therapeutic innovations addressing this growing global health challenge.

As metabolic liver diseases continue to afflict millions worldwide, advancements such as those presented in this study are essential. They not only decode complex biological interactions but also translate into tangible clinical benefits through precision medicine. The sex disparity unveiled here serves as a reminder that nuanced, mechanistically guided approaches are crucial in developing effective treatments tailored to individual biological contexts.

Ongoing efforts to target GPR110 could revolutionize the management of MASH and potentially other metabolic conditions with sex-linked disparities. Such breakthroughs herald a new era of personalized hepatology, emphasizing hormone receptor crosstalk and receptor pharmacology as frontlines in combating metabolic syndrome’s hepatic manifestations. This study thus represents a beacon of hope amid the escalating global burden of liver disease.

Subject of Research: Sex-specific mechanisms in metabolic dysfunction-associated steatohepatitis involving hepatic GPR110 and estrogen receptor alpha signaling.

Article Title: Hepatic GPR110 contributes to sex disparity in the development of MASH through oestrogen receptor α-dependent signalling.

Article References:
Yang, F., Wang, W., Qiu, F. et al. Hepatic GPR110 contributes to sex disparity in the development of MASH through oestrogen receptor α-dependent signalling. Nat Metab (2026). https://doi.org/10.1038/s42255-025-01436-1

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s42255-025-01436-1