Schisandrin C Targets PPARγ to Induce Ferroptosis in Colorectal Cancer Cells and Promote M1 Macrophage Polarization.
TL;DR
SinC improved survival, inhibited tumor growth, alleviated colonic pathology, exhibited biochemical features consistent with ferroptosis, and increased intratumoral CD86+ cell infiltration in CAC model, support SinC as a promising therapeutic candidate for CRC.
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.