Targeting STARD10 Alleviates Steatotic Liver Injury by Suppressing YBX1/ACSL1-Mediated Ferroptosis

Steatotic donor livers exhibit high graft failure rates after transplantation, primarily because of their increased vulnerability to ischemia‒reperfusion injury (IRI), in which ferroptosis serves as a critical pathological mechanism. STARD10, an evolutionarily conserved member of the steroidogenic acute regulatory lipid transfer (START/StARd) domain-containing protein family, is a hepatic-enriched lipid transport protein that mediates phospholipid transport and modulates plasma membrane composition and fluidity. However, the role of STARD10 in hepatic IRI under steatotic conditions and its potential direct relationship with ferroptosis-driven lipid peroxidation remain poorly understood.

The correlation between STARD10 expression and the severity of liver injury was first assessed in clinical liver transplant recipients. A mouse model of metabolic dysfunction-associated steatotic liver disease (MASLD) was established using a high-fat diet (HFD), followed by the induction of hepatic IRI. Hepatic STARD10 expression was modulated through adeno-associated virus serotype 8 (AAV8)-mediated delivery and CRISPR/Cas9. Liver injury was evaluated by histopathological examination, serum transaminase assays, and inflammatory response profiling. Mechanistic insights were obtained through integrated multiomic analyses, including lipidomics, transcriptomics, co-immunoprecipitation followed by mass spectrometry (IP-MS), and functional validation studies, which collectively elucidated the role of STARD10 in promoting IRI in steatotic livers.

STARD10 expression is significantly upregulated in steatotic donor livers and is positively correlated with the severity of ischemia-reperfusion injury after transplantation. In murine models, hepatocyte-specific knockout of STARD10 markedly attenuated IRI-induced hepatic pathology, including necrosis, inflammation, apoptosis, and reactive oxygen species generation, whereas its overexpression exacerbated these injuries. Interestingly, STARD10 deficiency suppressed ferroptosis, as indicated by diminished accumulation of polyunsaturated fatty acid-containing sphingolipids rather than phospholipids, reduced iron deposition, and improved mitochondrial function. Mechanistically, loss of STARD10 promoted the nuclear translocation of Y-box binding protein 1 (YBX1), which bound to the promoter region of and transcriptionally repressed acyl-CoA synthetase long-chain family member 1 (ACSL1). The subsequent downregulation of ACSL1 led to decreased levels of long-chain polyunsaturated sphingolipids and attenuated lipid peroxidation, thereby inhibiting the ferroptosis cascade. Finally, the overexpression of ACSL1 largely abolished the protective effects of STARD10 knockout against IRI and ferroptosis in steatotic livers.

Our study revealed that STARD10 is a key inducer of steatotic liver IRI via the YBX1-ACSL1 signaling axis. Targeting this pathway presents a novel therapeutic strategy to protect marginal livers from transplantation-associated injury.