Capsaicin ameliorates diabetic nephropathy by targeted activation of GPX4 and inhibition of pyroptosis.
- 1Department of Nephrology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
- 2Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
Abstract
Purpose
Capsaicin (CAP) is the primary pungent alkaloid found in chili peppers. The aim of this study is to screen for candidate therapeutic agents targeting the mitochondrial dysfunction-pyroptosis axis in diabetic nephropathy (DN) and to validate the efficacy and mechanism of action of capsaicin.Methods
Bioinformatics analysis was conducted to identify candidate genes and drugs. The protective effects and underlying mechanisms of CAP were investigated using a high-glucose (HG)-induced HK-2 cell model and a streptozotocin-induced T1DM DN rat model. Experimental techniques included CCK8 assay, flow cytometry (pyroptosis and ROS), JC-1 staining, Western blot analysis, and histopathological staining. GPX4-IN-3 was applied in vivo and in vitro to determine whether it reversed the protective effects of capsaicin. The data were analyzed using the Shapiro-Wilk test, one-way analysis of variance (ANOVA) with corresponding post-hoc tests, and correlation analysis.Results
Bioinformatic analysis identified 12 intersecting genes and highlighted CAP as a potential GPX4-targeting compound. Molecular docking demonstrated a high binding affinity of CAP for GPX4 and caspase-9. In vitro, CAP dose-dependently restored cell viability and suppressed HG-induced pyroptosis in HK-2 cells. It significantly alleviated mitochondrial damage by reducing ROS production, restoring mitochondrial membrane potential, and improving mitochondrial ultrastructure. Notably, these protective effects were reversed by GPX4-IN-3. Western blot analysis revealed that CAP upregulated GPX4 expression and inhibited activation of the NLRP3/caspase-1/GSDMD-N pyroptosis pathway. In vivo, CAP treatment markedly improved renal histopathology and renal function in DN rats; however, these effects were attenuated by co-administration of GPX4-IN-3.Conclusion
This study demonstrates that CAP ameliorates diabetic renal injury by targeting GPX4, thereby mitigating mitochondrial dysfunction and subsequent NLRP3-mediated pyroptosis. These findings validate the bioinformatic prediction and reveal a novel mechanism of action for CAP, positioning it as a promising therapeutic candidate for DN.
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BibTeX
@article{zhang2026capsaicin,
title = {{Capsaicin ameliorates diabetic nephropathy by targeted activation of GPX4 and inhibition of pyroptosis.}},
author = {Congqin Zhang and Xiaorong Wang and Fang Zhang and Chunhui Li and Xue Zhao and Sinan Zhao and Jing Liu and Sumin Jiao and Yongmei Hao},
journal = {Frontiers in endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1937280},
url = {https://europepmc.org/article/MED/42908587},
note = {CC BY},
}
RIS
TY - JOUR
TI - Capsaicin ameliorates diabetic nephropathy by targeted activation of GPX4 and inhibition of pyroptosis.
AU - Congqin Zhang
AU - Xiaorong Wang
AU - Fang Zhang
AU - Chunhui Li
AU - Xue Zhao
AU - Sinan Zhao
AU - Jing Liu
AU - Sumin Jiao
AU - Yongmei Hao
PY - 2026
DA - 2026/10/07
JO - Frontiers in endocrinology
DO - 10.3389/fendo.2026.1937280
UR - https://europepmc.org/article/MED/42908587
AB - Purpose Capsaicin (CAP) is the primary pungent alkaloid found in chili peppers. The aim of this study is to screen for candidate therapeutic agents targeting the mitochondrial dysfunction-pyroptosis axis in diabetic nephropathy (DN) and to validate the efficacy and mechanism of action of capsaicin.Methods Bioinformatics analysis was conducted to identify candidate genes and drugs. The protective effects and underlying mechanisms of CAP were investigated using a high-glucose (HG)-induced HK-2 cell model and a streptozotocin-induced T1DM DN rat model. Experimental techniques included CCK8 assay, flow cytometry (pyroptosis and ROS), JC-1 staining, Western blot analysis, and histopathological staining. GPX4-IN-3 was applied in vivo and in vitro to determine whether it reversed the protective effects of capsaicin. The data were analyzed using the Shapiro-Wilk test, one-way analysis of variance (ANOVA) with corresponding post-hoc tests, and correlation analysis.Results Bioinformatic analysis identified 12 intersecting genes and highlighted CAP as a potential GPX4-targeting compound. Molecular docking demonstrated a high binding affinity of CAP for GPX4 and caspase-9. In vitro, CAP dose-dependently restored cell viability and suppressed HG-induced pyroptosis in HK-2 cells. It significantly alleviated mitochondrial damage by reducing ROS production, restoring mitochondrial membrane potential, and improving mitochondrial ultrastructure. Notably, these protective effects were reversed by GPX4-IN-3. Western blot analysis revealed that CAP upregulated GPX4 expression and inhibited activation of the NLRP3/caspase-1/GSDMD-N pyroptosis pathway. In vivo, CAP treatment markedly improved renal histopathology and renal function in DN rats; however, these effects were attenuated by co-administration of GPX4-IN-3.Conclusion This study demonstrates that CAP ameliorates diabetic renal injury by targeting GPX4, thereby mitigating mitochondrial dysfunction and subsequent NLRP3-mediated pyroptosis. These findings validate the bioinformatic prediction and reveal a novel mechanism of action for CAP, positioning it as a promising therapeutic candidate for DN.
SN - 1664-2392
ER -