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Article

Caloric Restriction Mimetic Hydroxycitrate Mitigates Acute Nephrotoxicity via Autophagy Activation and Oxidative Stress Reduction

by
Xinyu Liao
1,2,
Nadezda V. Andrianova
1,
Ljubava D. Zorova
1,
Anna A. Brezgunova
1,
Kseniia S. Cherkesova
1,3,
Marina I. Buyan
1,2,
Dmitry S. Semenovich
1,
Alexandra A. Dalina
4,
Irina B. Pevzner
1,
Juan Jin
5,
Yunguang Wang
5 and
Egor Y. Plotnikov
1,*
1
A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
2
Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia
3
Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
4
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
5
Department of Nephrology, Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou 310006, China
*
Author to whom correspondence should be addressed.
Biomolecules 2026, 16(4), 538; https://doi.org/10.3390/biom16040538
Submission received: 8 February 2026 / Revised: 24 March 2026 / Accepted: 31 March 2026 / Published: 4 April 2026
(This article belongs to the Section Cellular Biochemistry)
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Abstract

Drug-induced nephrotoxicity is a leading cause of acute kidney injury (AKI) and subsequent chronic kidney disease. Nephrotoxicity often develops as a consequence of treatment with commonly prescribed aminoglycoside antibiotics, and remains a significant clinical challenge. One approach to treating AKI and its associated complications is caloric restriction or its pharmacological mimetics. This study aimed to evaluate the effects of caloric restriction mimetic hydroxycitrate (HC) in gentamicin-induced nephrotoxicity, with particular focus on the influence of treatment duration and the underlying molecular mechanisms. In vitro renal tubular epithelial cells models were used to assess HC’s effects on viability, proliferation, and autophagy activation. For in vivo validation, rats with gentamicin-induced AKI received HC treatment via two distinct regimens (3-week and 7-week administration). Experiments on renal tubule cells showed that HC significantly increased cell viability and proliferation and led to the activation of autophagy. In the rat model, only the 7-week administration of HC demonstrated significantly attenuated renal dysfunction in gentamicin-induced AKI. Moreover, it reduced macrophage infiltration, increased renal cell tolerance to apoptosis, activated autophagy, and reduced oxidative stress. Thus, our results indicate that 7-week HC administration could be used as a prophylactic strategy against antibiotic nephrotoxicity, exerting its effects by promoting autophagy, resisting apoptosis, and attenuating oxidative damage.
Keywords: caloric restriction; caloric restriction mimetics; acute kidney injury; inflammation; autophagy; mitochondria; oxidative stress; apoptosis caloric restriction; caloric restriction mimetics; acute kidney injury; inflammation; autophagy; mitochondria; oxidative stress; apoptosis

Share and Cite

MDPI and ACS Style

Liao, X.; Andrianova, N.V.; Zorova, L.D.; Brezgunova, A.A.; Cherkesova, K.S.; Buyan, M.I.; Semenovich, D.S.; Dalina, A.A.; Pevzner, I.B.; Jin, J.; et al. Caloric Restriction Mimetic Hydroxycitrate Mitigates Acute Nephrotoxicity via Autophagy Activation and Oxidative Stress Reduction. Biomolecules 2026, 16, 538. https://doi.org/10.3390/biom16040538

AMA Style

Liao X, Andrianova NV, Zorova LD, Brezgunova AA, Cherkesova KS, Buyan MI, Semenovich DS, Dalina AA, Pevzner IB, Jin J, et al. Caloric Restriction Mimetic Hydroxycitrate Mitigates Acute Nephrotoxicity via Autophagy Activation and Oxidative Stress Reduction. Biomolecules. 2026; 16(4):538. https://doi.org/10.3390/biom16040538

Chicago/Turabian Style

Liao, Xinyu, Nadezda V. Andrianova, Ljubava D. Zorova, Anna A. Brezgunova, Kseniia S. Cherkesova, Marina I. Buyan, Dmitry S. Semenovich, Alexandra A. Dalina, Irina B. Pevzner, Juan Jin, and et al. 2026. "Caloric Restriction Mimetic Hydroxycitrate Mitigates Acute Nephrotoxicity via Autophagy Activation and Oxidative Stress Reduction" Biomolecules 16, no. 4: 538. https://doi.org/10.3390/biom16040538

APA Style

Liao, X., Andrianova, N. V., Zorova, L. D., Brezgunova, A. A., Cherkesova, K. S., Buyan, M. I., Semenovich, D. S., Dalina, A. A., Pevzner, I. B., Jin, J., Wang, Y., & Plotnikov, E. Y. (2026). Caloric Restriction Mimetic Hydroxycitrate Mitigates Acute Nephrotoxicity via Autophagy Activation and Oxidative Stress Reduction. Biomolecules, 16(4), 538. https://doi.org/10.3390/biom16040538

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