Letter to the Editor: Unveiling a novel vitamin D receptor signaling pathway for allyl isothiocyanate against metabolic dysfunction-associated steatotic liver disease

Abstract

Gao et al published a study in World Journal of Gastroenterology present compelling in vitro evidence that allyl isothiocyanate (AITC), a natural compound from cruciferous vegetables, alleviates hepatic steatosis by activating the vitamin D receptor (VDR) and its downstream hepatocyte nuclear factor 4 alpha/microsomal triglyceride transfer protein/apolipoprotein B signaling pathway. This work identifies a novel mechanism of AITC, extending beyond the previously reported sirtuin 1/AMP-activated protein kinase pathway, and establishes VDR signaling as a promising therapeutic target for metabolic dysfunction-associated steatotic liver disease. Although the study demonstrates a clear association between AITC treatment and VDR pathway activation in hepatocytes, establishing direct causality through genetic VDR-knockout models remains necessary. Additionally, the therapeutic potential and safety profile of AITC must be evaluated in physiologically relevant in vivo models to advance its clinical translation. This research suggests new avenues for exploring the interplay between dietary compounds and nuclear receptor signaling in metabolic liver diseases.

Key Words: Allyl isothiocyanate; Metabolic dysfunction-associated steatotic liver disease; Vitamin D receptor; Lipid metabolism; Fatty acid β-oxidation; Insulin resistance

Core Tip: Gao et al identify a novel pathway for allyl isothiocyanate-mediated improvement of metabolic dysfunction-associated steatotic liver disease, involving the activation of the vitamin D receptor (VDR) signaling pathway in hepatocytes. We further propose that transient receptor potential ankyrin 1-mediated calcium signaling may act upstream of VDR activation, offering an alternative mechanistic insight. Future work needs to give priority to validating causality, particularly through VDR-knockout models and well-characterized in vivo models, such as high-fat diet or genetic metabolic dysfunction-associated steatotic liver disease models. This would allow researchers to evaluate the impact of allyl isothiocyanate, which is crucial for therapeutic translation.

TO THE EDITOR

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a considerable global health burden, with rising prevalence linked to obesity and metabolic syndrome. Despite its significant burden, effective therapeutic options remain limited[1,2]. We read with great interest the recent paper published in World Journal of Gastroenterology by Gao et al[3]. The authors conducted a series of well-designed in vitro experiments using alpha mouse liver 12 cells exposed to palmitic acid to establish a MASLD model. Their results demonstrate that allyl isothiocyanate (AITC) treatment significantly reduces lipid accumulation by downregulating lipogenesis-related genes, including SREBP1 and ACC1[4-6], while upregulating fatty acid β-oxidation genes such as PPARα and CPT1a[7,8]. Notably, Gao et al[3] revealed that AITC boosts vitamin D receptor (VDR) expression and activates the downstream hepatocyte nuclear factor 4 alpha/microsomal triglyceride transfer protein/apolipoprotein B signaling pathway, which plays a crucial role in hepatic lipid metabolism[9-11].

This newly proposed mechanism provides new insights into the current understanding of AITC’s roles. For instance, earlier work by Li et al[4] reported that AITC ameliorates hepatic lipid accumulation and inflammation in MASLD models via the sirtuin 1/AMP-activated protein kinase and nuclear factor kappa-B signaling pathways. When considered together with the present findings, these studies suggest that AITC likely operates through a multi-target network of molecular interactions rather than a single pathway. Key questions emerge regarding the relative contribution of the VDR/hepatocyte nuclear factor 4 alpha/microsomal triglyceride transfer protein/apolipoprotein B axis compared to the sirtuin 1/AMP-activated protein kinase pathway in ameliorating hepatic steatosis and inflammation, and whether synergistic or antagonistic crosstalk occurs between these mechanisms.

While such multi-target engagement could explain the compound’s robust therapeutic effects, it also raises important questions regarding the potential for off-target activities or complex, unpredictable systemic responses in vivo. Therefore, the proposed VDR-related pathway by Gao et al[3] warrants further investigation to clarify the primary drivers of its therapeutic benefits from potential secondary or compensatory effects. To strengthen the translational relevance of these findings, future research should focus on in vivo validation using preclinical models of MASLD/metabolic dysfunction-associated steatohepatitis. It will be important to evaluate whether the proposed mechanism is maintained in a more complex, system-level environment and to conduct thorough toxicological profiling to evaluate the potential for off-target effects. AITC is a well-characterized agonist of the transient receptor potential ankyrin 1 (TRPA1) channel[12]. TRPA1 activation leads to calcium ion influx, which has been shown to influence VDR expression and nuclear translocation[13]. Therefore, the observed “activation” of VDR by AITC could be an indirect consequence of TRPA1-mediated calcium signaling rather than a direct ligand-receptor interaction. Delineating the potential role of TRPA1 in this cascade is a crucial next step.

Furthermore, while the alpha mouse liver 12 cell model is suitable for initial mechanistic inquiry, it inherently lacks the complex liver microenvironment characteristic of MASLD. This microenvironment involves critical crosstalk among hepatocytes, immune cells, hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells. Notably, studies indicate that VDR expression is relatively low in parenchymal hepatocytes but significantly higher in non-parenchymal cells, including Kupffer cells, liver sinusoidal endothelial cells, HSCs, and cholangiocytes. The VD/VDR pathway influences hepatic lipogenesis and bile acid circulation in hepatocytes[14], mitigates inflammation by modulating hepatic macrophage polarization[10,15], maintains immune homeostasis via regulation of T lymphocytes and other immune cells[16], and suppresses liver fibrosis by inhibiting HSC activation[17]. Given this cell-type-specific signaling, a deeper exploration of the VDR signaling axis in the context of intercellular communication would offer a more holistic understanding of its therapeutic potential.

CONCLUSION

In conclusion, Gao et al[3] have made a noteworthy contribution by identifying VDR activation as a novel pathway in AITC-mediated improvement of MASLD. To expand on this work, we propose the following research directions to deepen the mechanistic understanding and therapeutic translation: (1) Establish causality: Employ siRNA or CRISPR/Cas9-mediated VDR knockdown/knockout in hepatocytes to definitively test the dependency of AITC’s effects on VDR; (2) Elucidate upstream mechanisms: Investigate the potential intermediary role of TRPA1 and calcium signaling in linking AITC to VDR activation; and (3) Validate in vivo: Assess the efficacy and safety of AITC in a preclinical animal model to confirm its therapeutic potential against MASLD. Addressing these points will strengthen our understanding of AITC’s molecular actions and support its potential as a therapeutic agent for MASLD.