Compound Kushen injection improves M1 macrophage polarisation and radiation-induced colitis by regulating Piezo1-mediated NF-κB/NLRP3 pathway

Background: Radiation-induced colitis (RIC) is a common complication following radiotherapy for pelvic and abdominal malignancies. Dysregulated polarisation of macrophages towards the pro-inflammatory classically activated M1 phenotype is a key driver of RIC progression.

Purpose: This study sought to examine the protective influence of compound Kushen injection (CKI) against RIC and clarify the mechanisms underlying these protective effects.

Methods and results: Mice were subjected to whole-abdominal irradiation (14 Gy) to model the clinical characteristics of RIC. The mice in the treatment groups received intraperitoneal injections of different doses of CKI for 3 days before exposure to ionising radiation (IR) and were euthanised 7 days after IR. CKI significantly increased the survival rate, body weight, and colon length of IR mice, and it ameliorated the IR-induced tissue damage, intestinal barrier disruption, elevated inflammatory factor levels, macrophage infiltration, and M1 polarisation. Mechanistically, CKI markedly suppressed Piezo1 activation and expression in macrophages as well as the Piezo1-mediated activation of the nuclear factor kappa B (NF-κB) and the NOD-like Receptor family pyrin domain containing 3 (NLRP3) inflammasome. Notably, macrophage-specific Piezo1 ablation significantly attenuated the therapeutic efficacy of CKI through impaired mechanosensing, while concomitantly diminishing the magnitude of M1 polarisation and blunting NF-κB/NLRP3 signalling transduction.

Conclusion: In conclusion, our findings demonstrated that CKI can improve RIC by modulating the Piezo1-mediated NF-κB/NLRP3 pathway and macrophage polarisation, thereby identifying a potential therapeutic target for RIC management and pharmacological intervention.