Neutrophil-derived TNF-α triggers ACSL4-mediated lipid peroxidation in post-hepatectomy liver injury.

BACKGROUND

Post hepatectomy liver failure (PHLF) is associated with high mortality. However, its pathophysiology remains unclear. This study explores the interactions among inflammation, fatty acids, and lipid peroxidation in the development of PHLF.

METHODS

Using mouse models of 70% (regeneration) and 86% (failure) partial hepatectomy, we examined neutrophil activity, TNF-α signaling, CD36-mediated palmitic acid transport, and ACSL4-dependent lipid peroxidation. Neutrophils were depleted via anti-Ly6G antibodies, and TNF-α, CD36 and ACSL4 were inhibited by etanercept, sulfosuccinimidyl oleate sodium and PRGL493, respectively. The analyses included transcriptomics, immunofluorescence, immunohistochemistry, flow cytometry, and oxidative stress assessments.

RESULTS

The 86% hepatectomy model showed marked neutrophil infiltration and TNF-α release at 6 h and 1 day post-surgery. Neutrophil depletion reduced TNF-α, attenuated liver injury, and improved survival in the 86% model. TNF inhibition (Etanercept) decreased hepatic lipid accumulation and oxidative stress, enhancing survival. TNF-α elevated palmitic acid in hepatocytes, whereas etanercept reduced it. TNF-α promotes palmitic acid accumulation through CD36-mediated fatty acid uptake rather than de novo Lipogenesis. Palmitic acid enhanced lipid peroxidation and mortality, while ACSL4 expression increased in response to both TNF-α and palmitic acid. ACSL4 inhibition lessened oxidative injury and improved outcomes.

CONCLUSION

Neutrophil-derived TNF-α drives hepatic palmitic acid accumulation and ACSL4-dependent lipid peroxidation, promoting liver injury after extensive hepatectomy. Targeting TNF-α or ACSL4 mitigates oxidative stress and improves survival, suggesting a therapeutic approach for preventing PHLF.