Hyperoside from Abelmoschus manihot Restores Mitochondrial Function and Reprograms Lipid Metabolism in Proximal Tubular Epithelial Cells via the ACAT1-L-Carnitine-SIRT3 Axis to Attenuate Renal Fibrosis

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Abstract Title *

Hyperoside from Abelmoschus manihot Restores Mitochondrial Function and Reprograms Lipid Metabolism in Proximal Tubular Epithelial Cells via the ACAT1-L-Carnitine-SIRT3 Axis to Attenuate Renal Fibrosis

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Co-author 1

Weilong Xu xwl@njucm.edu.cn Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine Department of Endocrinology Nanjing China *

Co-author 2

Chuchu Shan shanchuchu@njucm.edu.cn Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine Department of Endocrinology Nanjing China -

Co-author 3

Tamas Szili-Torok t.szili-torok@outlook.nl University Medical Center Groningen, University of Groningen, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine Division Nephrology, Department of Internal Medicine Groningen Netherlands -

Co-author 4

Jiangyi Yu yjy02105@njucm.edu.cn Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine Department of Endocrinology Nanjing China -

Co-author 5

Xiqiao Zhou zhouxiqiao@njucm.edu.cn Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine Department of Endocrinology Nanjing China -

Co-author 6

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Introduction

Renal fibrosis is a hallmark of chronic kidney disease (CKD) and it is closely associated with mitochondrial dysfunction and oxidative stress. Hyperoside is a flavonoid glycoside from Abelmoschus Manihot and it has antifibrotic effects in several organs. However, the potential protective role of hyperoside in renal fibrosis remains unknown.To investigate if hyperoside alleviates renal fibrosis through reprogramming lipid metabolism and restoring mitochondrial homeostasis, and to provide preclinical evidence for supporting its further development as a novel mitochondria-targeted therapy for CKD.

Methods

Mouse models of unilateral ureteral obstruction (UUO) and folic acid–induced nephropathy (FAN) were used to evaluate hyperoside’s effects on renal function, fibrosis, and mitochondrial integrity. Transcriptomic, metabolomic, and biochemical analyses were performed to identify key pathways. Molecular docking, cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) confirmed hyperoside’s direct interaction with ACAT1. Functional studies involving siRNA knockdown of Acat1 and supplementation with L-carnitine assessed the role of the ACAT1-L-carnitine axis. SIRT3 activity, oxidative stress markers, and mitophagy-related proteins were examined to explore downstream antioxidant mechanisms.

Results

Hyperoside significantly attenuated renal fibrosis and mitochondrial dysfunction in UUO and FAN models. Transcriptomic and metabolomic analyses revealed restoration of ACAT1 expression and reactivation of lipid metabolism pathways. Hyperoside directly bound and stabilized ACAT1, enhancing its enzymatic activity and promoting L-carnitine-dependent fatty acid oxidation. This metabolic reprogramming activated SIRT3-mediated deacetylation of SOD2, reduced reactive oxygen species (ROS) accumulation, and enhanced mitophagy. Knockdown of Acat1 abolished hyperoside’s protective effects, which were partially rescued by L-carnitine supplementation.

Conclusion

Hyperoside protects against renal fibrosis by targeting the ACAT1-L-carnitine-SIRT3 axis to restore mitochondrial metabolism and antioxidant defense. These findings provide new insights into hyperoside’s mechanism of action and suggest its potential as a mitochondrial-targeted therapy for CKD.

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