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

Area of Science:

• Molecular Biology
• Immunology
• Gastroenterology

Background:

• Stanniocalcin-1 (STC1) is linked to inflammation and oxidative stress.
• Parthanatos is a programmed necrotic cell death pathway dependent on PARP1 activation.
• The role of STC1 in colitis and parthanatos remains unclear.

Purpose of the Study:

• To investigate the function of STC1 in colitis and stress-induced parthanatos.
• To elucidate the molecular mechanisms underlying STC1's role in inflammation and cell death.

Main Methods:

• Analysis of STC1 expression in human Crohn's disease (CD) patients and mouse colitis models.
• Assessment of parthanatos severity and cytokine expression in STC1 knockout and overexpression models.
• Co-immunoprecipitation, mass spectrometry, and proteomic analyses to identify STC1 interacting partners.
• Inhibition of PARP1 and JNK pathways.
• Adeno-associated virus-mediated gene restoration and overexpression.

Main Results:

• STC1 expression is significantly increased in inflamed colonic mucosa of CD patients and colitis models.
• Intestinal-specific STC1 knockout mice are resistant to DSS-induced colitis, showing reduced disease severity.
• STC1 overexpression enhances parthanatos and pro-inflammatory cytokine expression, while STC1 knockout reduces them.
• STC1 interacts with PARP1, activating the JNK pathway.
• Inhibition of PARP1 and JNK alleviates STC1-induced parthanatos and inflammation.
• Restoration or overexpression of STC1 and PARP1 aggravates DSS-induced colitis.

Conclusions:

• STC1 exacerbates inflammation and parthanatos in colitis through the STC1-PARP1-JNK pathway.
• STC1 plays a critical role in Crohn's disease pathogenesis by mediating oxidative stress-induced cell death and inflammation.