Efficacy, safety, and mitochondrial mechanisms of myricetin in a preclinical model of trastuzumab-resistant HER2+ breast cancer.

Trastuzumab resistance remains a major clinical barrier in the treatment of HER2-positive breast cancer. To identify therapeutic candidates capable of overcoming resistance, we established trastuzumab-resistant derivatives of SKBR3 and BT474 cells and performed a high-throughput screen of a modified ChemDiv Natural Product-Based Library. Myricetin emerged as a top hit with selective anti-survival activity against resistant cells while sparing normal breast epithelial cells. Mechanistic studies revealed that myricetin selectively suppressed mitochondrial complex I activity without affecting complex II and III function, leading to marked reductions in basal and maximal respiration, diminished oxidative phosphorylation capacity, and significant depletion of intracellular ATP and induction of oxidative stress. Mitochondrial respiration-deficient ρ0 cells were less sensitive to myricetin, confirming that its cytotoxicity is at least partly mitochondria-dependent. In vivo, myricetin significantly inhibited the growth of trastuzumab-resistant xenograft tumors and reduced mitochondrial respiratory activity in freshly excised tumor tissues. Myricetin was well tolerated, with stable body weight, normal serum-biochemical parameters, and no detectable systemic toxicity. Importantly, myricetin treatment significantly prolonged survival in resistant xenograft-bearing mice. Collectively, these findings identify myricetin as a promising mitochondrial-targeting compound capable of overcoming trastuzumab resistance in HER2+ breast cancer and support its further development as a therapeutic candidate.