Schisandrin C Targets PPARγ to Induce Ferroptosis in Colorectal Cancer Cells and Promote M1 Macrophage Polarization

ABSTRACT Colorectal cancer (CRC) remains a leading cause of cancer mortality, necessitating novel therapeutic strategies. Schisandrin C (SinC), a bioactive lignan from Schisandra chinensis , exhibits diverse pharmacological activities, but its anti‐CRC mechanisms are poorly understood. This study investigated the anti‐CRC mechanism of SinC, focusing on PPARγ‐mediated ferroptosis and macrophage polarization. Network pharmacology predicted core targets and pathways. Direct SinC‐PPARγ binding was confirmed by molecular docking, CETSA, and luciferase reporter assays. In HCT116 and LoVo cells, proliferation, migration, and ferroptosis were evaluated, with mechanistic validation using a PPARγ agonist, antagonist, and shRNA. M1/M2 markers in RAW264.7 macrophages were detected. In an AOM/DSS‐induced CAC mouse model, ferroptosis and macrophage polarization were assessed by Prussian blue staining, immunohistochemistry, and Western blotting. SinC directly bound and activated PPARγ, concentration‐dependently inhibiting CRC cell proliferation, migration, and colony formation while inducing ferroptosis—effects reversed by liproxstatin. Mechanistically, SinC activated PPARγ, suppressed JAK2/STAT3 signaling, and downregulated SLC7A11/GPX4, effects enhanced by a PPARγ agonist and abolished by PPARγ antagonist or shRNA. SinC upregulated M1 markers and pro‐inflammatory cytokines, with a predominant M1‐associated activation pattern. In CAC model, SinC improved survival, inhibited tumor growth, alleviated colonic pathology, exhibited biochemical features consistent with ferroptosis, and increased intratumoral CD86 + cell infiltration. SinC directly binds and activates PPARγ transcriptional activity, inducing ferroptosis in CRC cells via the PPARγ‐JAK2/STAT3‐SLC7A11/GPX4 axis while concurrently promoting M1 macrophage polarization, exerting a dual antitumor effect. These findings support SinC as a promising therapeutic candidate for CRC.