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

Abstract

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.

Keywords

MASLD / OCM / primary liver cancer / sex differences / precision medicine

References

[1] Li Z,Tang Y,Tang Z.MASLD: an emerging factor in the pathophysiology and clinical management of ICC.Hepatoma Res2024;10:41

[2] Suzuki A,Reed MC.Lower hepatic CBS and PEMT expression in advanced NAFLD: inferencing strategies to lower homocysteine with a mathematical model.Metab Target Organ Damage2024;4:21

[3] Lugari S,Lonardo A.Metabolic primary liver cancer in adults: risk factors and pathogenic mechanisms.Metab Target Organ Damage2023;3:5

[4] Llovet JM,Singal AG.Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment.Nat Rev Gastroenterol Hepatol2023;20:487-503

[5] Gaull G,Schaffner F.Homocystinuria due to cystathionine synthase deficiency: enzymatic and ultrastructural studies.J Pediatr1974;84:381-90

[6] Torres L,Rodríguez JA.Induction of TIMP-1 expression in rat hepatic stellate cells and hepatocytes: a new role for homocysteine in liver fibrosis.Biochim Biophys Acta1999;1455:12-22

[7] Loscalzo J.The oxidant stress of hyperhomocyst(e)inemia.J Clin Invest1996;98:5-7 PMCID:PMC507392

[8] Werstuck GH,Dayal S.Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways.J Clin Invest2001;107:1263-73 PMCID:PMC209295

[9] Upchurch GR Jr,Fabian AJ.Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase.J Biol Chem1997;272:17012-7

[10] Jakubowski H.Metabolism of homocysteine thiolactone in human cell cultures: possible mechanism for pathological consequences of elevated homocysteine levels.J Biol Chem1997;272:1935-42

[11] Gulsen M,Bagci S.Elevated plasma homocysteine concentrations as a predictor of steatohepatitis in patients with non-alcoholic fatty liver disease.J Gastroenterol Hepatol2005;20:1448-55

[12] Ai Y,Peng C,Xiao X.Homocysteine induces hepatic steatosis involving ER stress response in high methionine diet-fed mice.Nutrients2017;9:346 PMCID:PMC5409685

[13] Liang H,Song X.Orphan nuclear receptor NR4A1 suppresses hyperhomocysteinemia-induced hepatic steatosis in vitro and in vivo.FEBS Lett2019;593:1061-71

[14] Yan Y,Wang P.Homocysteine promotes hepatic steatosis by activating the adipocyte lipolysis in a HIF1α-ERO1α-dependent oxidative stress manner.Redox Biol2020;37:101742 PMCID:PMC7559542

[15] Tripathi M,Zhou J.Vitamin B₁₂ and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation.J Hepatol2022;77:1246-55

[16] Bagherieh M,Zamani-Garmsiri F,Meshkani R.Folic acid ameliorates palmitate-induced inflammation through decreasing homocysteine and inhibiting NF-κB pathway in HepG2 cells.Arch Physiol Biochem2023;129:893-900

[17] Wang Meng,Yang Anning.Effect of macrophage PDHA1 gene knockout on apoptosis of hepatocytes in mice with non-alcoholic fatty liver disease.Chin J Pathophysiol2023;39:123-30

[18] Xiang W,Weng L.Hyperhomocysteinemia activates NLRP3 inflammasome to cause hepatic steatosis and insulin resistance via MDM2-mediated ubiquitination of HSF1.Int Immunopharmacol2023;118:110085

[19] Kim R,Reed MC.One-carbon metabolism during the menstrual cycle and pregnancy.PLoS Comput Biol2021;17:e1009708 PMCID:PMC8741061

[20] Balakrishnan M,Dunn-Valadez S.Women have a lower risk of nonalcoholic fatty liver disease but a higher risk of progression vs men: a systematic review and meta-analysis.Clin Gastroenterol Hepatol2021;19:61-71.e15 PMCID:PMC8796200

[21] Cherubini A,Della Torre S.Sex-specific effects of PNPLA3 I148M.Liver Int2025;45:e16088 PMCID:PMC11815604

[22] Vilar-Gomez E,Sookoian S.Impact of the association between PNPLA3 genetic variation and dietary intake on the risk of significant fibrosis in patients with NAFLD.Am J Gastroenterol2021;116:994-1006 PMCID:PMC8087619

[23] Lonardo A,Ballestri S.Sex differences in nonalcoholic fatty liver disease: state of the art and identification of research gaps.Hepatology2019;70:1457-69 PMCID:PMC6766425

[24] Núñez-Sánchez MÁ,Sierra-Cruz M.Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction-associated steatotic liver disease.J Pathol2024;264:101-11 PMCID:PMC11300153

[25] Satriano L,Rodrigues PM,Andersen JB.Metabolic rearrangements in primary liver cancers: cause and consequences.Nat Rev Gastroenterol Hepatol2019;16:748-66

[26] Lu M,Xia M.The role of metabolic reprogramming in liver cancer and its clinical perspectives.Front Oncol2024;14:1454161 PMCID:PMC11602425

[27] Mejia JC.Primary liver cancers: intrahepatic cholangiocarcinoma and hepatocellular carcinoma.Surg Clin North Am2020;100:535-49

[28] Lopez-Pascual A,Ardaiz N.Non-mitogenic FGF19 mRNA-based therapy for the treatment of experimental metabolic dysfunction-associated steatotic liver disease (MASLD).Clin Sci2024;138:1265-84