基于NLRP3/Caspase-1/GSDMD经典途径介导的肝实质细胞焦亡探讨活性维生素D对砷致肝纤维化损伤的干预作用及机制

地方性砷中毒除典型皮肤损伤外尚存在不同程度肝损伤，申请人前期研究亦显示砷暴露可显著诱导体外肝星状细胞（HSC）活化及大鼠肝纤维化损伤，但其具体机制目前尚未明确，且缺乏有效治疗手段。近期报道均发现NLRP3/Caspase1/GSDMD经典途径介导的细胞焦亡可能是肝纤维化发生发展的关键分子事件，然而其是否参与砷致肝纤维损伤目前未见报道。维生素D（Vit D）是人体必需脂溶性维生素，流行病学研究显示肝纤维化患者体内普遍存在Vit D缺乏，另有研究报道Vit D可通过VDR调控NLRP3介导的细胞焦亡逆转多种疾病发生发展。然而，活性Vit D是否可拮抗砷致肝纤维化损伤，其拮抗机制是否与NLRP3介导的细胞焦亡有关目前均不清楚。本项目拟通过体内外两个层面探讨NLRP3经典途径介导的肝实质细胞焦亡在活性Vit D干预砷致肝纤维化损伤的作用及机制，为砷中毒肝损伤患者的针对性防治及营养干预提供新策略。

In addition to typical skin lesions, endemic arsenicosis also showed different degrees of liver injury, our previous studies also confirmed that arsenic exposure can significantly induce hepatic stellate cells (HSC) activation and liver fibrosis in rats, but its specific mechanism is not yet clear, and there is also a lack of effective treatment measure. Recent reports have found that the classical pathway of NLRP3/Caspase1/GSDMD mediated pyroptosis may be a key molecular event in the development of liver fibrosis. However, whether NLRP3 mediated pyroptosis is involved in the process of arsenic-induced liver fibrosis has not been reported yet. Vitamin D (Vit D) is an essential fat-soluble vitamin for human body, a large number of epidemiological studies have shown that Vit D deficiency is significantly related to liver fibrosis, and various studies also have reported that Vit D can reverse the occurrence and development of many diseases by regulating NLRP3-mediated pyroptosis through binding to VDR. However, it is not clear whether Vit D can antagonize arsenic-induced liver fibrosis, and whether its antagonistic mechanism is related to NLRP3-mediated pyroptosis is also unclear. On the basis of our previous studies, this project intends to systematically explore the role and mechanism of NLRP3/Caspase1/GSDMD mediated pyroptosis in the intervention effects of active Vit D on arsenic-induced liver fibrosis through both in vivo and in vitro studies, which could provide new strategies for scientific prevention and nutritional intervention of liver injury caused by endemic arsenicosis.