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Stanniocalcin‐1 Promotes PARP1‐Dependent Cell Death via JNK Activation in Colitis

Liguo Zhu,Zhuo Xie,Guang Yang,Gaoshi Zhou,Li Li,Shenghong Zhang

Published 2023 in Advancement of science

ABSTRACT

Stanniocalcin‐1 (STC1) is upregulated by inflammation and modulates oxidative stress‐induced cell death. Herein, the function of STC1 in colitis and stress‐induced parthanatos, a newly identified type of programmed necrotic cell death dependent on the activation of poly‐ADP ribose polymerase‐1 (PARP1) is investigated. Results show that STC1 expression is markedly increased in the inflamed colonic mucosa of Crohn's disease (CD) patients and chemically‐induced mice colitis models. Evaluation of parthanatos severity and pro‐inflammatory cytokine expression shows that intestinal‐specific Stc1 knockout (Stc1INT‐KO) mice are resistant to dextran sulfate sodium (DSS)‐induced colitis and exhibit lower disease severity. STC1‐overexpressing cells show an increased degree of parthanatos and proinflammatory cytokine expression, whereas STC1‐knockout cells show a decreased degree of parthanatos. Co‐immunoprecipitation, mass spectrometry, and proteomic analyses indicate that STC1 interacts with PARP1, which activates the JNK pathway via PARP1–JNK interactions. Moreover, inhibition of PARP1 and JNK alleviates parthanatos and inflammatory injuries triggered by STC1 overexpression. Finally, following restoration of Stc1 and Parp1 expression by adeno‐associated viruses, and overexpression of Stc1 and Parp1 aggravated DSS‐induced colitis in Stc1INT‐KO mice. In conclusion, STC1 mediates oxidative stress‐associated parthanatos and aggravates inflammation via the STC1–PARP1–JNK interactions and subsequent JNK pathway activation in CD pathogenesis.

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