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Background: Post-hepatectomy liver failure (PHLF) is a fatal complication of hepatectomy. However, the mechanism of hepatocyte injury in PHLF remains elusive., Methods: PHLF was induced by extended 86% hepatectomy (eHx) in mice. Lipidomics was performed to investigate the eHx-induced lipid alteration in the residual liver. Ferroptosis was assessed to screen the hepatocyte injury induced by eHx. The therapeutic effects of ferrostatin-1 (Fer-1) on PHLF were evaluated., Results: PHLF was induced by eHx with elevation in markers of hepatocyte injury and mortality in mice within 48 h after surgery. eHx-induced hepatocyte injury was manifested by hepatocyte enlargement and hepatocyte death with glycogen depletion and lipid accumulation. Lipidomics revealed that eHx induced the accumulation of ferroptosis-favored polyunsaturated lipids. Ferroptosis was found to mediate the eHx-induced hepatocyte death in the residual liver during the development of PHLF. Fer-1 could attenuate the eHx-induced ferroptotic hepatocyte death and PHLF in mice., Conclusions: Ferroptosis partly mediates the eHx-induced hepatocyte injury during the development of PHLF. Accumulation of polyunsaturated lipids in hepatocytes may promote eHx-induced ferroptosis, and targeting lipid peroxidation is a potential therapeutic strategy for PHLF.

Background & Aims: Transient regeneration-associated steatosis (TRAS) is a process of temporary hepatic lipid accumulation and is essential for liver regeneration by providing energy generated from fatty acid β-oxidation, but the regulatory mechanism underlying TRAS remains unknown. Parkinsonism-associated deglycase (Park7)/Dj1 is an important regulator involved in various liver diseases. In nonalcoholic fatty liver diseased mice, induced by a high-fat diet, Park7 deficiency improves hepatic steatosis, but its role in liver regeneration remains unknown METHODS: Park7 knockout (Park7 -/- ), hepatocyte-specific Park7 knockout (Park7 △hep ) and hepatocyte-specific Park7-Pten double knockout mice were subjected to 2/3 partial hepatectomy (PHx) RESULTS: Increased PARK7 expression was observed in the regenerating liver of mice at 36 and 48 h after PHx. Park7 -/- and Park7 △hep mice showed delayed liver regeneration and enhanced TRAS after PHx. PPARa, a key regulator of β-oxidation, and carnitine palmitoyltransferase 1a (CPT1a), a rate-limiting enzyme of β-oxidation, had substantially decreased expression in the regenerating liver of Park7 △hep mice. Increased phosphatase and tensin homolog (PTEN) expression was observed in the liver of Park7 △hep mice, which might contribute to delayed liver regeneration in these mice because genomic depletion or pharmacological inhibition of PTEN restored the delayed liver regeneration by reversing the downregulation of PPARa and CPT1a and in turn accelerating the utilization of TRAS in the regenerating liver of Park7 △hep mice CONCLUSION: Park7/Dj1 is a novel regulator of PTEN-dependent fatty acid β-oxidation, and increasing Park7 expression might be a promising strategy to promote liver regeneration., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Rationale and Objectives: Posthepatectomy liver failure (PHLF) remains challenging to diagnose and difficult to treat. The extent of transient regeneration-associated steatosis (TRAS) differs between successful liver regeneration and PHLF. This study aims to quantify TRAS by magnetic resonance imaging (MRI) after hepatectomy in mice., Materials and Methods: Mice (C57BL/6) underwent either extended hepatectomy (EH) or standard hepatectomy (SH). Serial MRI on postoperative days 1-7 was used to compare TRAS and liver remnant growth between groups. Survival was also assessed., Results: EH was associated with decreased survival and impaired proliferation when compared to SH (p = 0.02 and p = 0.03). MRI showed increased TRAS 48 h after EH compared to SH (11.8 ± 6% vs. 4.3 ± 2%, p < 0.001). Compared to EH survivors, death after EH was associated with increased TRAS 48 h postoperatively (16.4 ± 6% vs. 9.2 ± 5%, p = 0.02)., Conclusions: EH is associated with increased TRAS and inferior outcomes when compared to SH. MRI may help to predict PHLF after hepatectomy., (Copyright © 2018 Elsevier Inc. All rights reserved.)