6''-O-acetylsaikosaponin D targets STAT3-mediated transcriptional remodeling to induce ferroptosis and apoptosis

  • Phytomedicine. 2026 Jul 25:157:158301. doi: 10.1016/j.phymed.2026.158301.
Xuehui Li  1 ,  Yunxiao Qiao  2 ,  Xinyi Xu  2 ,  Jinyu Zhu  2 ,  Chuang Xie  2 ,  Shan Lin  3 ,  Lingfan Xu  4 ,  Fuwen Yuan  5
Affiliations
  • 1. Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China; The Center for Cancer Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2. The Center for Cancer Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 3. Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China. Electronic address: [email protected].
  • 4. Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230001, China. Electronic address: [email protected].
  • 5. The Center for Cancer Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: [email protected].
PMID: 42166974 DOI: 10.1016/j.phymed.2026.158301
Abstract

Background: Natural products from traditional medicinal Plants represent an important source of anti-cancer agents and lead compounds for drug development. Saikosaponin D (SSD), a triterpenoid saponin isolated from Radix Bupleuri, exhibits anti-tumor activity but is limited by a narrow therapeutic window and cytotoxicity.

Objective: This study aimed to evaluate the anti-tumor activity of 6''-O-acetylsaikosaponin D (6''-O-acSSD), a naturally occurring acetylated derivative of Saikosaponin D that is identified in Radix Bupleuri, and to elucidate its underlying molecular mechanisms.

Methods: The anti-cancer effects of 6''-O-acSSD were assessed using multiple Cancer cell models, three-dimensional tumor spheroids, and patient-derived tumor organoids. Transcriptomic and bioinformatic analyses were performed to identify regulated cell death pathways. Molecular docking, molecular dynamics simulation, cellular thermal shift assays, western blotting, and CUT&Tag profiling were used to identify molecular targets and define transcriptional reprogramming.

Results: 6''-O-acSSD markedly suppressed Cancer cell proliferation, migration, and invasion and elicited a transcriptional program distinct from that induced by SSD. Transcriptomic and biochemical analyses revealed preferential activation of ferroptosis-associated signatures, including enhanced lipid peroxidation. Mechanistically, 6''-O-acSSD engaged STAT3, inhibited its phosphorylation, and extensively remodeled STAT3 chromatin occupancy. Functional analyses showed that STAT3 inhibition was required for the full anti-tumor activity of 6''-O-acSSD. Notably, blockade of Ferroptosis only partially rescued cell viability, whereas STAT3 targeting additionally triggered apoptosis-associated transcriptional and biochemical changes. The anti-tumor effects of 6''-O-acSSD were further validated in patient-derived tumor organoids.

Conclusion: 6''-O-acSSD exerts potent anti-tumor effects by targeting STAT3-dependent transcriptional programs and inducing coordinated Ferroptosis and Apoptosis. These findings highlight the therapeutic potential of structurally optimized natural products for anti-cancer treatment.

Keywords
6′'-O-acetylsaikosaponin D; Apoptosis; Ferroptosis; Natural product derivatives; STAT3; Transcriptional reprogramming.
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