The roles and mechanisms of sulfur metabolism and disulfidptosis in metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex and increasingly prevalent condition whose pathogenesis involves multiple interacting factors, yet the precise molecular mechanisms remain incompletely understood. This review proposes that dysregulated sulfur metabolism and disulfidptosis, mediated by solute carrier family 7 member 11 (SLC7A11), act synergistically to drive MASLD progression. Accumulating evidence suggests that abnormal sulfur metabolism not only exacerbates liver injury through oxidative stress but also creates a distinct pathological state. Under conditions of NADPH depletion and disrupted intracellular redox balance, the compensatory overexpression of SLC7A11, initially intended to maintain antioxidant defense, paradoxically triggers disulfidptosis. This model is supported by multiple lines of evidence: exogenous factors, including dietary sulfur intake, environmental sulfur dioxide (SO2) exposure, and genetic polymorphisms, significantly increase MASLD risk by disrupting sulfur metabolic homeostasis. Concurrently, aberrant expression of disulfidptosis-related genes (DRGs) in the livers of patients with MASLD promotes a vicious cycle of disease progression by disrupting metabolic balance and remodeling the hepatic immune microenvironment. The "sulfur metabolism-disulfidptosis axis" conceptual framework proposed herein delineates the intricate crosstalk between these processes, thereby providing novel insights into MASLD pathogenesis.