TO THE EDITOR
Metabolic dysfunction-associated steatotic liver disease (MASLD) and aging processes are interconnected through specific pathological pathways, including cellular senescence, lipid metabolism dysregulation, and ferroptosis induction. These mechanisms collectively drive disease progression and amplify liver injury, thereby placing increasing demands on global healthcare resources. In a novel study, Zhu et al[1] unveiled the pivotal role of vitamin D receptor (VDR) in aging-related MASLD, significantly advancing our comprehension of its pathophysiology and unveiling novel targets for intervention. The researchers demonstrated that VDR expression is increased in aged hepatic tissue and senescent hepatocytes, and its genetic ablation attenuated hepatic steatosis and insulin resistance in preclinical models. The elevation of VDR expression in these models is particularly significant because it might be a driving factor in the progression of MASLD, as suggested by the observed accumulation of lipids.
Moreover, aging is associated with increased levels of cellular senescence markers, which are linked to dysfunctional lipid metabolism. This disrupted lipid metabolism can trigger ferroptosis, a form of cell death that exacerbates liver injury. Aging promotes the pathological progression of MASLD through multifactorial mechanisms, including elevated cellular senescence marker levels, increased VDR expression, dysregulated lipid metabolism, ferroptosis induction, exacerbated inflammatory responses, and aggravated insulin resistance[2,3], with these pathways synergistically amplifying hepatic lipotoxicity and cellular stress[4]. The aforementioned article proposed that VDR modulates metabolic reprogramming by regulating the lipid oxidation-related protein LIPIN1 and lipid synthesis-associated enzyme fatty acid synthase. These findings provide critical evidence for understanding the mechanisms and identifying therapeutic targets for aging-related MASLD.
Nevertheless, although the study identified a positive correlation between VDR and tumor protein 53 (P53) expression, the precise mechanism by which P53 regulates VDR transcription remains elusive. Clarifying the regulation of VDR by p53 could provide insights into the crosstalk between cellular senescence pathways and lipid metabolism, both of which are key factors in MASLD progression. Recent evidence suggests that P53 can influence target gene expression through epigenetic modifications such as promoter methylation, warranting further investigation using chromatin immunoprecipitation sequencing to validate direct transcriptional regulation[5]. MASLD is often characterized by lipid metabolic abnormalities, including increased fatty acid synthesis, impaired fatty acid oxidation, and cholesterol metabolic disorders[6,7]. These alterations both lead to hepatic steatosis and affect the functions of immune and stromal cells through metabolic reprogramming. Metabolic reprogramming, characterized by dynamic adaptations in carbohydrate, lipid, and amino acid metabolism, along with the activation of stress pathways such as endoplasmic reticulum stress, autophagy, and ferroptosis, is a defining feature of cellular phenotype transitions in MASLD[8]. These metabolic and stress adaptations collectively fuel the progression of inflammation and fibrosis in MASLD. Hepatic stellate cells (HSCs) play a pivotal role in inflammation-mediated insulin resistance. During liver injury, intricate interactions between hepatocytes and HSCs contribute to mitochondrial dysfunction, which subsequently promotes intracellular lipid accumulation in hepatocytes[9]. This pathological process ultimately leads to hepatic lipotoxicity through impaired lipid metabolism. Aging further exacerbates these lipid metabolic disturbances via mitochondrial dysfunction, creating a synergistic mechanism that intensifies metabolic dysregulation in the liver and associated cell populations[10].
In the livers of individuals with MASLD, multiple forms of cell death coexist, including pyroptosis, apoptosis, and necroptosis. Apoptosis is often considered a primary driver of hepatocellular injury in early MASLD, whereas ferroptosis can become more prominent as the disease progresses to steatohepatitis and fibrosis. Ferroptosis, an iron-catalyzed lethal accumulation of lipid peroxides, has been identified as a key modulator of necrotic cell death in MASLD pathogenesis[11]. Emerging evidence demonstrates that aging-related ferroptotic stress is correlated with elevated expression of senescence markers in hepatocytes[12]. Comparative studies revealed that aged murine livers exhibit heightened ferroptotic susceptibility, manifested by increased levels of lipid peroxidation byproducts and amplified inflammatory responses[13]. Significantly, pharmacological inhibition of ferroptosis has been found to mitigate aging-aggravated hepatic injury, identifying ferroptosis suppression as a potential therapeutic strategy for senescence-associated liver pathology.
Furthermore, although the current study provides valuable insights from cellular and animal models, its direct clinical relevance to human health remains to be established. Future clinical validation studies should employ prospective longitudinal cohorts of age-stratified patients with MASLD, with sample sizes powered to detect ≥ 20% intergroup differences in VDR activity, and prioritize clinical validation through single-center or multi-center cohorts of patients with MASLD[14,15]. Specifically, assessing the correlations of serum vitamin D metabolites with disease severity and progression, coupled with evaluations of hepatic VDR expression patterns, could determine whether the vitamin D status represents a robust predictive biomarker[16,17]. Such data would enhance risk stratification and guide personalized therapeutic decision-making, particularly in aging populations, which have a higher prevalence of MASLD.
In summary, future research on aging-related MASLD should adopt a multifaceted and hierarchical approach to address the complexity of the disease. In the near term, studies should focus on elucidating the epigenetic mechanisms of p53-VDR transcriptional regulation and clarifying the mechanism by which VDR signaling interacts with mitochondrial lipid metabolism. Over the medium term, research should evaluate the efficacy and safety of both VDR-targeted interventions and alternative strategies such as ferroptosis inhibition, possibly integrating these approaches into combination therapies. Long-term objectives should include developing personalized treatment algorithms that account for the heterogeneity of MASLD phenotypes and the varying contributions of different pathogenic pathways at distinct disease stages. Such a balanced agenda recognizes the limitations of single-target approaches and aligns with the multifactorial nature of aging-related MASLD, ultimately guiding more effective therapeutic development.
