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Page 2 of 8 Li et al. Metab Target Organ Damage. 2025;5:19 https://dx.doi.org/10.20517/mtod.2025.05

INTRODUCTION
Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD) currently exceeds a
[1]
30% global prevalence, making it a primary contributor to the contemporary burden of liver disease . In the
ongoing quest to elucidate MASLD pathogenesis, the emerging centrality of the one-carbon metabolism
(OCM) pathway and its regulatory product, homocysteine (Hcy), has become increasingly apparent.
Through mathematical modeling, Suzuki et al. substantiated that diminished expression of two key OCM
enzymes - cystathionine β-synthase (CBS) and phosphatidylethanolamine N-methyltransferase (PEMT) -
[2]
correlates significantly with the progression of hepatic fibrosis in individuals with MASLD . Their work
further indicates that strategic OCM cofactor supplementation may effectively modulate hepatic Hcy levels,
while highlighting the pivotal role of sex-related factors in both disease progression and therapeutic
response. Collectively, these findings point toward a new frontier in the stratified treatment of MASLD.

Moreover, given that MASLD has been identified as an independent risk factor for primary liver cancer
(PLC), including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) , the elucidation of
[3,4]
this metabolic pathway holds profound implications for the field of hepatobiliary surgery. The bidirectional
interplay between metabolic derangement and tumorigenesis is reshaping traditional surgical strategies. The
liver’s role as a central metabolic hub, coupled with the systemic nature of PLC, compels a critical
reappraisal of the limitations inherent in surgical resection alone. In the era of precision medicine,
integrating metabolic characteristics into preoperative assessment and implementing targeted metabolic
interventions during the perioperative period may fundamentally enhance both surgical outcomes and
patient prognosis.

Accordingly, this paper endeavors to systematically analyze the findings of Suzuki et al., sketch the
molecular landscape of the OCM-Hcy-MASLD axis, underscore the significance of sex-based modulation
[2]
within this continuum, and examine its transformative potential for PLC surgery . By highlighting these
insights, we strive to extend the reach of precision medicine into both the mechanistic understanding of
hepatic metabolic disorders and the evolving surgical strategies that address them.

ADVANCES IN CLINICS AND MECHANISM
The intersection of OCM and hepatic pathology was first documented in 1974 when Gaull et al. observed
hepatocellular enlargement and microvesicular steatosis in liver biopsies from patients with severe
hyperhomocysteinemia due to CBS deficiency . This association was mechanically confirmed by
[5]
Torres et al., who found that homocysteine induced TIMP-1 and K1(I) procollagen expression by activating
the AP-1 transcription factor, which may promote liver fibrosis . These seminal findings established the
[6]
foundational link between OCM dysregulation and hepatic lipid accumulation, suggesting potential
therapeutic implications for metabolic liver diseases.

Subsequent mechanistic investigations have elucidated four primary pathogenic pathways through which
[7]
OCM perturbation and Hcy elevation promote liver injury: oxidative stress induction , endoplasmic
reticulum stress activation , reduced nitric oxide bioavailability , and protein homocysteinylation-
[9]
[8]
mediated cellular dysfunction . These molecular mechanisms collectively contribute to hepatic
[10]
inflammation and fibrosis progression, highlighting the multifaceted role of the OCM-Hcy axis in MASLD
pathogenesis.
The clinical relevance of this pathway was further validated by Gulsen et al., who demonstrated a robust
correlation between serum Hcy levels and MASLD severity . Their findings established Hcy as an
[11]
independent risk factor for hepatic inflammation and fibrosis progression, providing a strong rationale for