Differential DNAm-GDF15 and mitochondrial profile in lean MAFLD.

Metabolic dysfunction associated fatty liver disease in people of healthy weight (so-called “lean” MAFLD) shows a comparably favorable clinical profile yet paradoxically has an increased risk of mortality. The underlying mechanisms for this phenomenon, especially their mitochondrial profiles, cellular stress responses and levels of Growth Differentiation Factor 15 (GDF15), a stress-responsive cytokine involved in mitochondrial function and metabolic regulation, and associated with adverse health outcomes, remains unclear. We examined the prognostic value of DNA methylation-predicted GDF15 (DNAm-GDF15) in relation to all-cause and cause-specific mortality, utilizing data from the National Health and Nutrition Examination Survey (NHANES). We assessed the mitochondrial profile and stress response in lean and non-lean MAFLD using murine dietary models and human liver biopsies. Lean MAFLD patients had higher DNAm-GDF15 levels (951.6 ± 151.7 vs. 918.9 ± 143.8; P = 0.01). Elevated DNAm-GDF15 was associated with increased all-cause (Q4 vs. Q1: HR 8.33; 95% CI, 6.84–10.15; P < 0.001) and cause-specific mortality risk. Lean MAFLD has a distinct mitochondrial profile characterised by increased size, impaired function, altered mitochondrial dynamics, augmented endoplasmic reticulum stress responses and reactive oxygen species (ROS) generation. Differences in DNAm-GDF15 levels and mitochondrial profile explain at least partially the paradox of increased mortality risk among individuals with lean MAFLD compared to their non-lean counterparts. It also offers new avenues for therapy to mitigate the risk. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10238-025-01976-6.