Berberine derivative C51 modulates cGAS-STING-TIM-3 axis to reverse immune evasion and inhibit lung cancer growth.

Berberine, also known as berberine hydrochloride, is an isoquinoline alkaloid extracted from natural plants, exhibiting a wide range of biological activities, including anti-inflammatory, antioxidant, antitumor, antibacterial, antiviral, and neuroprotective effects. However, its low oral absorption rate and poor bioavailability limit its clinical application. To address this issue, this study synthesized a novel Berberine derivative, C51, which significantly improves absorption rate and bioavailability while enhancing its antitumor activity. This study focused on the antitumor mechanism of C51 in lung cancer, particularly its ability to inhibit lung cancer cell proliferation, invasion, and migration by regulating the cGAS (Cyclic GMP-AMP Synthase)-STING (Transmembrane Protein 173) -TIM-3 (T-cell Immunoglobulin and Mucin Domain-containing Molecule 3) molecular axis. Experimental results demonstrated that C51 significantly inhibited lung cancer cell proliferation at very low concentrations, with its half-maximal inhibitory concentration (IC50) significantly lower than that of Berberine. Additionally, C51 exerted its antitumor effects by activating the cGAS-STING molecular axis and inhibiting the TIM-3 molecular axis. Silencing TIM-3 inhibits the proliferation and immune escape of lung cancer. Further molecular mechanism studies revealed that CGAS directly regulates the STING-TIM-3 molecular axis, while STING forms a chaperone relationship with TIM-3 and promotes TIM-3 degradation through the K48-dependent ubiquitination pathway, thereby suppressing the malignant phenotype of lung cancer cells. These findings not only reveal the antitumor mechanism of C51 but also provide new insights for the treatment of lung cancer. Animal experiments also demonstrated that C51 significantly inhibits the proliferation of subcutaneous xenograft tumors in mouse. As a novel Berberine derivative, C51 exhibits significant antitumor activity and inhibits lung cancer progression by regulating the CGAS-STING-TIM-3 molecular axis. This study lays an important theoretical foundation for the development of novel antitumor drugs based on C51, with significant clinical application potential. However, the long-term toxicity and safety of C51 require further investigation to establish safe dosage standards for clinical use. Future studies will focus on exploring combination therapy strategies of C51 in cisplatin-resistant lung cancer to provide new directions for precision treatment of lung cancer.