Metabolism, sex, and what lies beyond the scalpel in MASLD

The discovery of the one-carbon metabolism-homocysteine-metabolic dysfunction-associated steatotic liver disease (OCM-Hcy-MASLD) axis has renewed our understanding of MASLD-related primary liver cancer (PLC). Based on Suzuki et al.’s mathematical modeling findings of diminished cystathionine β-synthase (CBS) and phosphatidylethanolamine N-methyltransferase (PEMT) expression in MASLD, this commentary analyzes recent findings regarding sex-specific variations in this axis and their implications for surgical management. We highlight how the integration of OCM-Hcy pathway modulation with precise surgical interventions could enhance perioperative outcomes and long-term prognosis. The emerging evidence suggests that targeted metabolic interventions, particularly those accounting for sex differences, may complement traditional surgical approaches by addressing the systemic nature of MASLD-related PLC. This paradigm shift from purely surgical resection toward comprehensive metabolic regulation marks a significant advance in precision medicine for hepatobiliary surgery, potentially improving both perioperative safety and oncological outcomes.