Diosgenin presents a novel role in promoting diabetic wound healing: A mechanism involving Sirt6/Nrf2-mediated inhibition of ferroptosis

Ji-qi Wang; Lu Chen; Yu-zhe Lin; Xiu-zhi Zhang; Yi-tian Yu; Yi-han Lin; Li-jiang Han; Yi-yun Lv; Nai-feng Tian; Zhen Lin; Wei-jun Guo

doi:10.1016/j.jpha.2026.101635

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Ji-qi Wang, Lu Chen, Yu-zhe Lin, Xiu-zhi Zhang, Yi-tian Yu, Yi-han Lin, Li-jiang Han, Yi-yun Lv, Nai-feng Tian, Zhen Lin, Wei-jun Guo. Diosgenin presents a novel role in promoting diabetic wound healing: A mechanism involving Sirt6/Nrf2-mediated inhibition of ferroptosis[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2026.101635

Citation:

Ji-qi Wang, Lu Chen, Yu-zhe Lin, Xiu-zhi Zhang, Yi-tian Yu, Yi-han Lin, Li-jiang Han, Yi-yun Lv, Nai-feng Tian, Zhen Lin, Wei-jun Guo. Diosgenin presents a novel role in promoting diabetic wound healing: A mechanism involving Sirt6/Nrf2-mediated inhibition of ferroptosis[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2026.101635

Citation:

Ji-qi Wang, Lu Chen, Yu-zhe Lin, Xiu-zhi Zhang, Yi-tian Yu, Yi-han Lin, Li-jiang Han, Yi-yun Lv, Nai-feng Tian, Zhen Lin, Wei-jun Guo. Diosgenin presents a novel role in promoting diabetic wound healing: A mechanism involving Sirt6/Nrf2-mediated inhibition of ferroptosis[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2026.101635

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Diosgenin presents a novel role in promoting diabetic wound healing: A mechanism involving Sirt6/Nrf2-mediated inhibition of ferroptosis

doi: 10.1016/j.jpha.2026.101635

Ji-qi Wang^a,b,
Lu Chen^c,
Yu-zhe Lin^a,b,
Xiu-zhi Zhang^a,b,
Yi-tian Yu^d,
Yi-han Lin^c,
Li-jiang Han^a,b,
Yi-yun Lv^e,
Nai-feng Tian^{a,b
,
,},
Zhen Lin^{b,c
,
,},
Wei-jun Guo^{a,b
,
,}

a. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China;
b. Key Laboratory of Orthopaedics, Zhejiang Province, Wenzhou, Zhejiang, 325000, China;
c. Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China;
d. The First School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China;
e. The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China

Funds:

This work was funded by the Zhejiang Provincial Medical and Health Science and Technology Plan (Grant No.: 2025KY1014) and Wenzhou Science and Technology Bureau Project (Project No.: Y20210429).

Received Date: Nov. 05, 2025
Accepted Date: Apr. 13, 2026
Rev Recd Date: Apr. 12, 2026
Available Online: Apr. 14, 2026

Abstract

Abstract

Delayed wound healing in patients with diabetes is frequently caused by the dysfunction of human umbilical vein endothelial cells (HUVECs). Under high-glucose and high-fat (HGHF) conditions, the microenvironment induces uncontrolled lipid peroxidation and subsequent iron-dependent ferroptosis. Diosgenin (DG), a steroidal saponin extracted from herbs, including wild yam, exhibits diverse pharmacological activities. The present study aimed to investigate the role and underlying mechanism of DG in HGHF-induced ferroptosis and diabetic wound healing. A diabetic wound model was established in mice by intraperitoneal injection of streptozotocin. HUVECs were cultured under HGHF conditions to induce the diabetic microenvironment. C11-BODIPY, FerroOrange probes, and hematoxylin-eosin/Masson staining were used to determine lipid peroxidation, iron ion levels, and histological changes, respectively. Results demonstrated that DG alleviated HGHF-induced ferroptosis, as evidenced by reduced malondialdehyde (MDA), lipid peroxidation, and mitochondrial reactive oxygen species levels, and increased glutathione (GSH) levels. Additionally, DG upregulated the expression of the anti-ferroptotic protein glutathione peroxidase 4 (GPX4), promoted angiogenesis, and accelerated wound healing in diabetic mice. Network pharmacology analysis identified the sirtuin 6/nuclear factor erythroid 2-related factor 2 (Sirt6/Nrf2) pathway as a potential target of DG, a finding validated by mechanistic studies. Silencing Sirt6 in HUVECs negated the protective effect of DG against ferroptosis. In conclusion, DG mitigates ferroptosis and promotes diabetic wound healing, at least partially through activating the Sirt6/Nrf2 pathway.
- Diosgenin,
- Diabetic wounds,
- High-glucose and high-fat,
- Ferroptosis,
- Sirt6/Nrf2 pathway

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References(45)

References

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