Bisphenol A and Di-n-butyl phthalate disrupt bone homeostasis bidirectionally via CD36-mediated BMSCs autophagy inhibition and exosome-promoted osteoclastogenesis.

Bisphenol A (BPA) and di-n-butyl phthalate (DBP) are ubiquitous endocrine disruptors implicated in bone metabolism disorders, but their precise mechanisms remain unclear. Here, we demonstrated that BPA and DBP bidirectionally disrupt bone homeostasis by targeting CD36 in bone marrow-derived mesenchymal stem cells (BMSCs). Mechanistically, both chemicals upregulate CD36 expression, which sequesters ATG9a at the Golgi apparatus, inhibits autophagosome maturation, and thereby impairs osteogenic differentiation of BMSCs, as evidenced by reduced ALP and RUNX-2 levels. Exosomes from BPA-treated BMSCs contain elevated RANKL, NFATC1, and osteoclast-promoting miRNAs, driving RAW264.7 macrophages toward bone-resorbing osteoclast phenotypes. Importantly, siRNA-mediated CD36 knockdown in BMSCs restores autophagy, recovers osteogenic markers, normalizes exosomal cargo, and reduces osteoclastogenic potential. Furthermore, in vivo rat mandibular defect models validate that BPA exposure impairs bone repair, alters CD36-dependent autophagy and osteoclastogenesis, effects that were ameliorated by CD36 silencing. Collectively, these dual actions-autophagy inhibition in BMSCs and exosome-mediated osteoclastogenesis-converge to disturb bone remodeling, providing novel insights into the pathogenesis of endocrine disruptor-induced osteoporosis and identifying CD36 as a promising therapeutic target for preserving skeletal integrity.