Anti-tumor effects of Guggulsterone in osteosarcoma: Role of SIRT3-mediated PINK1-Parkin mitophagy activation

Lingyuan Zeng; Shuwei Li; Kaidong Wu; Xiaoyu Bai; Long Zhang

doi:10.1016/j.phymed.2026.157860

Anti-tumor effects of Guggulsterone in osteosarcoma: Role of SIRT3-mediated PINK1-Parkin mitophagy activation

Phytomedicine. 2026 Jan 20:153:157860. doi: 10.1016/j.phymed.2026.157860. Online ahead of print.

Authors

Lingyuan Zeng¹, Shuwei Li¹, Kaidong Wu², Xiaoyu Bai², Long Zhang³

Affiliations

¹ Department of Orthopedics, Second Clinical Medical College, Shanxi Medical University, Taiyuan 030001, PR China.
² Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Department of Orthopedics, Second Hospital of Shanxi Medical University, Taiyuan 030001, PR China.
³ Center for Rehabilitation Medicine, Department of Pain Management, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, PR China. Electronic address: zhanglong@hmc.edu.cn.

PMID: 41650525
DOI: 10.1016/j.phymed.2026.157860

Abstract

Osteosarcoma (OS) is an aggressive primary bone malignancy characterized by limited therapeutic options and poor prognosis in advanced stages. Guggulsterone (GS), a naturally occurring plant-derived sterol, has recently been reported to suppress OS progression by inhibiting glycolysis via the MAPK signaling pathway. Although these findings underscore the therapeutic potential of GS in OS, the contribution of mitochondrial quality control to its antitumor activity remains unclear. Here, we report that GS disrupts mitochondrial integrity, elevates oxidative stress, and drives enhanced mitophagy in OS cells. RNA sequencing combined with functional assays revealed significant enrichment of mitophagy-related pathways, while rescue experiments confirmed that blocking mitophagy or SIRT3 activity markedly alleviated GS-induced mitochondrial damage, apoptosis, and growth inhibition. Mechanistically, GS activated the SIRT3-dependent PINK1/Parkin axis in a time-dependent manner, providing compelling evidence for its involvement in mitophagy regulation. Importantly, GS markedly inhibited OS tumor growth in vivo without causing detectable systemic toxicity. Collectively, our findings identify a mechanism distinct from the previously reported glycolysis/MAPK pathway, thereby broadening the mechanistic understanding of GS and underscoring its potential as a mitochondria-targeted therapeutic strategy for OS.

Keywords: Guggulsterone; Mitophagy; Osteosarcoma; PINK1-Parkin; SIRT3.