Bariatric surgery may alleviate MASLD by restoring mitochondria-lipid droplet structural and functional integrity through suppression of the Mitochondrial Fission Factor-Perilipin 5 axis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most prevalent chronic liver diseases worldwide, characterized primarily by excessive lipid droplet (LD) accumulation in hepatocytes. Bariatric surgery, particularly sleeve gastrectomy (SG), represents the most effective intervention for reversing MASLD, although the underlying mechanisms remain incompletely understood. This study aimed to investigate the mitochondrial and lipid droplets (LDs) related molecular mechanisms by which SG ameliorated MASLD. Using a high-fat diet (HFD)-induced mouse model of MASLD, combined with SG intervention, hepatocyte-specific genetic manipulation, multi-omics analysis, and mitochondrial ultrastructural examination, we observed that MASLD was associated with a marked upregulation of perilipin 5 (PLIN5) on the LD surface and mitochondrial fission factor (MFF) on the mitochondrial outer membrane. Ultrastructural and co-immunoprecipitation (Co-IP) analyses revealed that PLIN5 and MFF formed a complex that facilitated the recruitment of LDs to mitochondria and their penetration into the mitochondrial matrix. This process ultimately led to disrupted mitochondrial fatty acid β-oxidation and structural disorganization. SG significantly downregulated PLIN5 and MFF expression, reduced LD-induced mitochondrial damage, and enhanced mitochondrial resilience to high-fat stress. These changes might contribute to the restoration of mitochondria-LD structural and functional homeostasis, ultimately reversing MASLD. Our findings indicated that aberrant upregulation of MFF contributed to MASLD progression, and SG might alleviate the disease by suppressing the MFF-PLIN5 axis to normalize mitochondria-LD interactions. These results suggested that targeting the MFF-PLIN5 axis may offer a promising therapeutic strategy for non-surgical management of MASLD.