Background & Aims: Liver fibrosis is characterized by the progressive scarring of liver tissue. Oxidative stress is a critical causal factor of hepatic stellate cell (HSC) activation and the subsequent liver fibrogenesis, but the mechanism is not fully understood. Cysteine sulfinic acid (Cys-SO2H), a modification of reactive cysteine residues, is a unique form of oxidative response that alters the structure and function of proteins. Sulfiredoxin 1 (SRXN1) is responsible for ATP-dependent reduction of the Cys-SO2H to sulfenic acid (Cys-SOH). Approach & Results: We found that the expression of SRXN1 was increased in activated HSCs and in human and mouse fibrotic livers. HSC-specific ablation of Srxn1 or pharmacological inhibition of Srxn1 exacerbated HSC activation and sensitized mice to liver fibrosis. Mechanistically, SRXN1 inhibited HSC activation by de-sulfinylating the phosphatase protein tyrosine phosphatase non-receptor type 12 (PTPN12), which enhanced its phosphatase activity and protein stability, leading to decreased tyrosine phosphorylation and reduced activation of the pro-fibrotic inflammasome protein NLRP3. The anti-fibrotic effect of SRXN1 was abolished when NLRP3 was inhibited. In contrast, overexpression of PTPN12 attenuated NLRP3 activation, and this effect was further amplified by the C164A S-sulfinylation resistant mutant of PTPN12. Conclusions: Our findings have uncovered an important role of SRXN1 and protein S-sulfinylation in HSC activation and liver fibrosis. The SRXN1-PTPN12-NLRP3 axis represents potential therapeutic targets for liver fibrosis.

中文翻译：

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去亚磺酰化酶 sulfiredoxin-1 通过调节 PTPN12-NLRP3 轴减弱肝星状细胞活化和肝纤维化


背景和目标：肝纤维化的特点是肝组织逐渐形成疤痕。氧化应激是肝星状细胞 （HSC） 活化和随后的肝纤维化的关键致病因素，但其机制尚不完全清楚。半胱氨酸亚磺酸 （Cys-SO2H） 是反应性半胱氨酸残基的一种修饰，是一种独特的氧化反应形式，可改变蛋白质的结构和功能。磺胺氧还蛋白 1 （SRXN1） 负责 ATP 依赖性地将 Cys-SO2H 还原为亚磺酸 （Cys-SOH）。方法和结果：我们发现SRXN1在活化的HSCs以及人和小鼠纤维化肝脏中的表达增加。Srxn1 的 HSC 特异性消融或 Srxn1 的药理学抑制加剧了 HSC 活化并使小鼠对肝纤维化敏感。从机制上讲，SRXN1 通过对磷酸酶蛋白酪氨酸磷酸酶非受体 12 型 （PTPN12） 进行去磺化来抑制 HSC 活化，从而增强其磷酸酶活性和蛋白质稳定性，导致酪氨酸磷酸化降低和促纤维化炎性小体蛋白 NLRP3 的激活降低。当 NLRP3 被抑制时，SRXN1 的抗纤维化作用被消除。相反，PTPN12 的过表达减弱了 NLRP3 的激活，并且这种作用被 PTPN12 的 C164A S-亚砾化抗性突变体进一步放大。结论： 我们的研究结果揭示了 SRXN1 和蛋白 S-亚砾酰化在 HSC 活化和肝纤维化中的重要作用。SRXN1-PTPN12-NLRP3 轴代表肝纤维化的潜在治疗靶点。