Bazedoxifene and Beyond: Identifying This SERM's Targets and Deciphering Its Molecular Mechanisms.

Bazedoxifene (BZA), a third-generation selective estrogen receptor modulator (SERM) approved for osteoporosis treatment, is attracting attention for drug repurposing, especially in cancer research. While designed primarily for estrogen receptors, BZA exhibits in vitro off-target interactions that may explain novel therapeutic benefits or account for potential side effects. This review comprehensively examines both established and newly identified targets of BZA beyond estrogen receptors. To gather relevant data, we reviewed over 1500 articles selecting key studies proposing insights into BZA targets and mechanisms. This review details BZA's roles in estrogen receptor signaling and its interactions with glycoprotein 130, elaborating on vital components of each signaling pathway. It also compiles its potential interactions with cannabinoid receptors, as well as BZA targets related to biotransformation, absorption/transport, DNA cycle, Sars-CoV-2, ferroptosis, ROS production, and cholesterol biosynthesis. For each target, we discuss evidence from computational studies, direct interaction assay, and functional testing. This work provides the most complete overview of BZA's molecular mechanisms to date and suggests new avenues for future research and potential applications beyond osteoporosis.