Isorhamnetin (ISO) is an active flavonoid compound mainly isolated from the fruits of Hippophae rhamnoides L. and the leaves of Ginkgo biloba L. Previous studies have revealed the antifibrotic action of ISO in the liver and lungs, although its potential protective effects against renal fibrosis and the underlying mechanisms are still poorly understood. Given that many actions of ISO could be similarly attained by hydrogen sulfide (H₂S), we speculated that ISO may work through the induction of endogenous H₂S. To test the hypothesis, we established the unilateral ureteral obstruction (UUO) renal fibrosis rat model and transforming growth factor-β1(TGF-β1)-induced fibrosis in cultured renal tubular cells. ISO treatment inhibited epithelial–mesenchymal transition (EMT) formation, decreased extracellular matrix (ECM) deposition, and relieved renal fibrosis. Further analysis revealed that ISO stimulated the expression of the H₂S-synthesizing enzyme cystathionine lyase (CSE) and cystathionine beta-synthase (CBS), and promoted H₂S production in vivo and in vitro. The elevated H₂S attenuated oxidative stress and elevated the thiol level. It induced Keap1 sulfhydration, disrupted Keap1-Nrf2 interaction, and promoted the entry of Nrf2 into the nucleus. Finally, we found that circulating H₂S mainly derived from the liver, and not the kidney. Collectively, our study revealed that ISO alleviated renal fibrosis by inducing endogenous H₂S and regulating Keap1-Nrf2 interaction through sulfhydration of Keap1. Endogenous H₂S could be an important mediator underlying the pharmacological actions of ISO. Due to the multifunctional properties of H₂S, the H₂S-inducing nature of ISO could be exploited to treat various diseases.

Palmitoylation is a critical post-translational modification that involves the covalent binding of palmitic acid to cysteine residues within proteins. It is widely recognized that palmitoylation plays a significant role in regulating protein membrane localization, stability, and interactions. The kidney plays a key role in maintaining fluid homeostasis and excreting metabolic waste, and its normal function relies on the precise regulation of protein function. Emerging evidence reveals the crucial role of palmitoylation in renal physiological and pathological processes. However, the intricate pathways and molecular regulators in the kidney that are involved in palmitoylation remain insufficiently elucidated. This review summarizes the role and possible underlying physiological and pathological mechanism of palmitoylation in the kidney, including enzymes and inhibitors that regulate palmitoylation, the signaling pathways involved, target proteins involved in palmitoylation, and specific modification sites. Moreover, we focus on detection techniques and corresponding research strategies for palmitoylation. This review can also serve as a practical reference to improve the understanding of palmitoylation and the treatment of kidney-related diseases.