Mangiferin targeting HSP90α induces DNA damage in cutaneous squamous cell carcinoma via the ROS/MAPK signaling pathway

Cutaneous squamous cell carcinoma (cSCC) is a common type of skin tumor with high incidence and significant disease burden. Current clinical treatments face challenges such as high recurrence rates and drug resistance, making the discovery of novel drugs and therapeutic targets critically important. Previous studies have confirmed that Mangiferin(MF) can inhibit the proliferation of various tumors, promote apoptosis, and regulate cellular oxidative stress. This study investigated the therapeutic effects and mechanisms of MF in cutaneous squamous cell carcinoma (cSCC). CCK-8 and EDU assays demonstrated that MF significantly inhibited A431 cell proliferation, induced apoptosis, and caused G0/G1 phase arrest. Network pharmacology, molecular docking, and molecular dynamics simulations identified HSP90α as a direct target of MF, which was highly expressed in clinical cSCC tissues and validated through CETSA and DARTS experiments. Genetic manipulation experiments revealed that HSP90α knockdown promoted apoptosis, while its overexpression accelerated proliferation and attenuated MF's effects. Mechanistically, MF induced ROS generation, leading to mitochondrial and DNA damage, which could be reversed by the antioxidant NAC. Furthermore, ROS-mediated activation of the MAPK pathway contributed to apoptosis and DNA damage. In vivo, MF effectively suppressed cSCC growth without causing organ toxicity. In conclusion, MF inhibits cSCC progression both in vitro and in vivo with minimal toxicity, primarily through targeting HSP90α and activating the ROS/MAPK pathway.