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Li et al. Metab Target Organ Damage. 2025;5:19 https://dx.doi.org/10.20517/mtod.2025.05 Page 3 of 8

therapeutic targeting of the OCM-Hcy axis in MASLD treatment. This clinical correlation has profound
implications for surgical decision making, as elevated Hcy levels may serve as a biomarker for disease
severity and surgical risk stratification.

Recent advances [12,18] have substantiated the causal relationship within the OCM-Hcy-MASLD axis
[Table 1], elucidating the regulatory effects of OCM cofactors on Hcy homeostasis and MASLD
progression. This emerging molecular landscape not only provides multiple therapeutic targets but also
highlights the promising therapeutic potential of OCM cofactor intervention strategies. The intricate
molecular mechanisms underlying the OCM-Hcy-MASLD axis have been progressively unveiled.

SEX-SPECIFIC REGULATION MATTERS
Although a growing body of literature now identifies the OCM-Hcy-MASLD axis as a key mediator of
hepatic injury, the sex-specific intricacies of these interlinked mechanisms have often been overlooked.
Most studies to date have not stratified participants by sex or age, limiting the ability to capture how
hormonal subpopulations might respond differently to OCM-targeted interventions.

Indeed, estrogens and androgens distinctly regulate key steps within the OCM-Hcy axis, exerting divergent
[19]
effects on critical enzymes . These divergent influences, in turn, translate into differing metabolic
landscapes for men and women, shaping both the natural history of MASLD. A prominent meta-analysis by
Balakrishnan et al. underscores this sexual dimorphism, revealing that while women have a 19% lower risk
of MASLD (formerly termed NAFLD), they exhibit a 37% higher risk of developing advanced fibrosis
[20]
compared with men . Notably, menopause at approximately age 50 modifies the effect of sex on disease
aggressiveness, with postmenopausal women facing elevated odds of MASH (metabolic dysfunction-
associated steatohepatitis, previously known as NASH) and advanced fibrosis. Emerging genetic evidence
suggests that this disparity is amplified by PNPLA3 variant interaction - the rs738409-CG polymorphism
shows a 40% higher penetrance of fibrosis in men . This was further supported by mechanistic findings
[21]
[22]
from Vilar-Gomez et al., who found that PNPLA3 risk variants disrupt hepatic methionine metabolism .
These findings collectively suggest that hormonal fluctuations exert profound effects on hepatic metabolism
and disease progression. Women may benefit from protective hormonal profiles during their
premenopausal years; yet, once this protective window closes, the subsequent rise in fibrotic burden may be
heightened by metabolic perturbations that were previously attenuated. Considering sex, age, and
reproductive status (e.g., menarche and menopause) is therefore emerging as a pivotal element in designing
[23]
precision medicine approaches for MASLD .
Against this backdrop, Suzuki et al. [Figure 1] take a bold step forward by pairing traditional clinical
insights with a sophisticated mathematical approach, offering more than a descriptive account of Hcy
dysregulation . Their simulations of distinct OCM cofactor regimens in men and women deliver practical
[2]
guidance on how vitamins B6, B12, folate, and betaine might be harnessed synergistically for maximum
Hcy-lowering impact. While prior studies have confirmed the importance of OCM cofactors in reducing
liver injury, the novelty of Suzuki et al.’s model lies in its capacity to capture subtle sex differences that
could otherwise remain obscured . Specifically, the data suggest that although folate alone confers a potent
[2]
Hcy-lowering effect in both sexes, combining all available cofactors consistently yields the greatest
reduction, hinting at untapped therapeutic synergies. This approach powerfully illustrates how theory-
driven modeling can accelerate translational research, refining our understanding of MASLD phenotypes
and illuminating personalized interventions.