ArticleOpen life sciences2025
Kynurenine facilitates renal cell carcinoma progression by suppressing M2 macrophage pyroptosis through inhibition of CASP1 cleavage.
Article in Open life sciences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Renal cell carcinoma (RCC) is an aggressive malignancy with a poor prognosis influenced by pyroptosis in tumor-associated M2 macrophages. This study investigated how kynurenine modulates pyroptosis in M2 macrophages and promotes RCC progression. M2 macrophages were treated with pyroptosis inhibitor VX-765 or kynurenine to evaluate their effects on cell viability and pyroptosis. Transwell co-culture systems were employed to assess the impact of M2 macrophages on RCC cell proliferation, colony formation, and viability. The interaction between kynurenine and CASP1 (caspase-1), a key executor of pyroptosis that cleaves gasdermin D (GSDMD) to trigger inflammatory cell death, was analyzed using surface plasmon resonance. The results demonstrated that VX-765 treatment significantly enhanced M2 macrophage viability while reducing pyroptosis, thereby promoting RCC cell proliferation in co-culture systems. Kynurenine significantly enhanced M2 macrophage viability while suppressing pyroptosis. Mechanistically, kynurenine reduced the cleavage of CASP1 (caspase-1) by directly binding to it. Overexpression of CASP1 reversed kynurenine-induced suppression of pyroptosis in M2 macrophages. Furthermore, CASP1 overexpression abolished kynurenine-mediated enhancement of RCC cell viability, colony formation, and proliferation. This study revealed that kynurenine inhibits pyroptosis in M2 macrophages via direct targeting of CASP1, creating a tumor-supportive microenvironment that accelerates RCC progression. These findings establish the kynurenine-CASP1 axis as a critical regulator of M2 macrophage pyroptosis and demonstrate its role in promoting RCC progression, identifying a potential therapeutic target for RCC treatment.
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