• PSRC1 expression is downregulated during macrophage pyroptosis, and its knockout exacerbates pyroptosis and inflammation.
• Overexpression of PSRC1 alleviates pyroptosis and inflammation in bone marrow-derived macrophages.
• PSRC1 negatively regulates the ECM component periostin (POSTN), and knockdown of POSTN suppresses pyroptosis in PSRC1-deficient macrophages.
• This study identifies PSRC1 as a potential therapeutic target for inflammatory diseases involving macrophage pyroptosis.