Diosmetin augments BRAF-targeted therapy via concurrent suppression of MAPK and STAT3 pathways in melanoma

Despite the well-established therapeutic benefits of BRAF inhibitors in prolonging progression-free survival (PFS) for melanoma patients with BRAF mutants, their long-term efficacy is often compromised by the emergence of acquired resistance, particularly through compensatory activation of Janus kinase 2/Signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. Confronting this challenge, concurrent inhibition of Mitogen-activated protein kinase (MAPK) and JAK2/STAT3 pathways offers a novel approach to overcome therapeutic resistance. Diosmetin (DIOS), a naturally occurring flavonoid compound, has a spectrum of bioactivities including antioxidant, anti-infective, and anti-tumor properties. In this study, we explored the antitumor effects of DIOS and evaluated its synergistic potential with BRAF inhibitors in melanoma treatment. Through comprehensive in vitro and in vivo analyses, we demonstrated that DIOS possessed potent antiproliferative effects against melanoma cells and significantly enhanced the antitumor activity of BRAF inhibitors by concurrently suppressing the MAPK and STAT3 pathways. Moreover, DIOS downregulated programmed cell death ligand 1 (PD-L1) expression in melanoma cells, thereby enhancing intratumoral T cell infiltration and activating antitumor immune responses. Collectively, our findings identify DIOS as a multifaceted therapeutic agent with dual-pathway inhibitory activity and immunomodulatory effects, supporting its potential as a clinically translatable adjuvant to BRAF-targeted therapies in BRAF-mutant melanoma.