Lymphocyte antigen 6 family member D (LY6D) was enhanced specifically in senescent cells, while its effects on pyroptosis, a programmed cell death, remains unknown. The goal of this study was to assess the role of LY6D in the mediation of pyroptosis during nonalcoholic steatohepatitis (NASH). After screening out LY6D as a specific liver fibrosis-associated gene using the GSE55747 dataset from the GEO database, we established a NASH mouse model using methionine and choline deficient-diet feeding and an in vitro model using lipopolysaccharide (LPS)-treated hepatocytes. LY6D was overexpressed in NASH livers as well as in LPS-treated hepatocytes. Silencing of LY6D inhibited NASH-associated hepatocyte pyroptosis. With the aid of bioinformatics analysis, promoter-luciferase reporter and ChIP-qPCR assays, we identified FOSL2 as an upstream transcription factor of LY6D. FOSL2, which was highly expressed in NASH, promoted LY6D transcription by binding to the promoter of LY6D. Depletion of FOSL2 significantly inhibited NASH-associated hepatocyte pyroptosis, which was significantly reversed after overexpression of LY6D. Moreover, the promotion of hepatocyte pyroptosis by the FOSL2/LY6D axis was significantly attenuated by specific inhibition of NLRP3. These findings suggesting that FOSL2/LY6D axis may be a key molecular axis and a potential target for NASH therapeutics.

淋巴细胞抗原 6 家族成员 D (LY6D) 在衰老细胞中特异性增强，而其对细胞焦亡（一种程序性细胞死亡）的影响仍然未知。本研究的目的是评估 LY6D 在介导非酒精性脂肪性肝炎 (NASH) 期间细胞焦亡中的作用。在使用 GEO 数据库中的 GSE55747 数据集筛选出 LY6D 作为特定肝纤维化相关基因后，我们建立了使用蛋氨酸和胆碱缺乏饮食喂养的 NASH 小鼠模型和使用脂多糖 (LPS) 处理的肝细胞的体外模型。LY6D 在 NASH 肝脏以及 LPS 处理的肝细胞中过表达。LY6D 的沉默抑制了 NASH 相关的肝细胞焦亡。借助生物信息学分析、启动子荧光素酶报告基因和 ChIP-qPCR 分析，我们将 FOSL2 鉴定为 LY6D 的上游转录因子。在 NASH 中高表达的 FOSL2 通过与 LY6D 的启动子结合来促进 LY6D 的转录。FOSL2 的消耗显着抑制了 NASH 相关的肝细胞焦亡，在 LY6D 过表达后显着逆转。此外，通过特异性抑制 NLRP3 显着减弱了 FOSL2/LY6D 轴对肝细胞焦亡的促进作用。这些发现表明 FOSL2/LY6D 轴可能是 NASH 治疗的关键分子轴和潜在靶点。NLRP3的特异性抑制显着减弱了FOSL2/LY6D轴对肝细胞焦亡的促进作用。这些发现表明 FOSL2/LY6D 轴可能是 NASH 治疗的关键分子轴和潜在靶点。NLRP3的特异性抑制显着减弱了FOSL2/LY6D轴对肝细胞焦亡的促进作用。这些发现表明 FOSL2/LY6D 轴可能是 NASH 治疗的关键分子轴和潜在靶点。