2. Academic Validation
  3. Genistein alleviates Osteoporosis by inhibiting the differentiation and autophagy of osteoclasts via regulating the CYLD/p62/RANKL axis

Genistein alleviates Osteoporosis by inhibiting the differentiation and autophagy of osteoclasts via regulating the CYLD/p62/RANKL axis

  • Biochem Biophys Res Commun. 2026 Apr 23:810:153457. doi: 10.1016/j.bbrc.2026.153457.
Jungao Zhu 1,  Xiaoqin Huang 1,  Chuanchuan Li 2,  Weixian Liu 3,  Xiaoqing Zhong 4
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Zhejiang Hospital, No. 1229 Gudun Road, West Lake District, Hangzhou City, Zhejiang Province, 310016, China.
  • 2 Department of Thoracic Surgery, Zhejiang Hospital, No. 1229 Gudun Road, West Lake District, Hangzhou City, Zhejiang Province, 310016, China.
  • 3 Department of Neurosurgery, Zhejiang Hospital, No. 1229 Gudun Road, West Lake District, Hangzhou City, Zhejiang Province, 310016, China.
  • 4 Department of Orthopaedics, Zhejiang Hospital, No. 1229 Gudun Road, West Lake District, Hangzhou City, Zhejiang Province, 310016, China. Electronic address: [email protected].
PMID: 41764819 DOI: 10.1016/j.bbrc.2026.153457
Abstract

Osteoporosis is a highly prevalent metabolic bone disorder characterized by an imbalance in bone remodeling, primarily due to excessive osteoclast-mediated bone resorption. The present study systematically investigates the protective effects of genistein, a naturally occurring soy isoflavone, against osteoporosis by targeting osteoclast differentiation and Autophagy, as well we the underlying mechanism. Using RANKL-stimulated RAW264.7 cells as an in vitro model, we found that genistein treatment significantly and dose-dependently inhibited osteoclast formation and autophagic activity, which was evidenced by reduced tartrate-resistant Acid Phosphatase (TRAP) activity, fewer autophagic vacuoles observed under transmission electron microscopy, decreased protein levels of LC3-II/I and Beclin1, and increased expression of p62. Mechanistic studies revealed that genistein upregulates the Deubiquitinase CYLD, which stabilizes p62 through deubiquitylation, leading to inhibition of the RANKL signaling pathway. Importantly, the anti-osteoclastogenic effects of genistein were markedly attenuated upon CYLD or p62 knockdown or upon induction of Autophagy with rapamycin. In an ovariectomized (OVX) rat model of postmenopausal osteoporosis, genistein administration (5 or 10 mg/kg/day) effectively ameliorated bone loss, as confirmed by micro-CT analyses showing improvements in bone mineral density (BMD), bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular separation (Tb.Sp). Consistent with in vitro findings, genistein reduced osteoclast numbers and modulated Autophagy markers in femoral tissues. Collectively, these results demonstrate that genistein mitigates osteoporosis by suppressing osteoclast differentiation and Autophagy through regulating the CYLD/p62/RANKL axis, highlighting its promising potential as a natural therapeutic agent for osteoporosis treatment.

Keywords

Autophagy; Deubiquitylation; Genistein; Osteoclasts; Osteoporosis.

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