Mechanistic insights into myricetin-regulated autophagy via the PI3K/Akt and PINK1/Parkin pathway in diabetic kidney disease treatment

Ethnopharmacological relevance

Rubus suavissimus S.Lee (RS), a traditional ethnomedicine Guangxi, China, has long been used to manage diabetes and its complications. Existing studies have demonstrated the antidiabetic activity of RS and its complications, but the pharmacological material basis and molecular mechanism of its efficacy have not been clarified.

Aim of the study

This study aimed to elucidate the active constituents and specific molecular mechanisms underlying the therapeutic effects of RS in diabetic kidney disease (DKD).

Materials and methods

Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to identify major active components within RS polyphenol extracts. Core signaling pathways and key active components were screened using network pharmacology analysis and enrichment methods. Subsequently, an in vitro MPC-5 podocyte cell model was established under high-glucose and high-lipid conditions. Data-independent acquisition (DIA) mass spectrometry was used to analyze differentially expressed proteins in the cellular secretome. Mitochondrial ultrastructure was assessed using transmission electron microscopy (TEM). Key protein expression changes were validated by Western blotting.

Results

Network pharmacology screening identified myricetin (Myr) as the compound exhibiting the highest binding affinity to PIK3R1, suggesting its role as a key active component in the anti-DKD effects of RS polyphenols. In vitro, high-glucose and high-lipid exposed MPC-5 cells exhibited pronounced mitochondrial swelling and cristae disruption. Myr treatment significantly preserved mitochondrial morphology and induced the formation of double-membrane autophagic vesicles encapsulating damaged mitochondria, indicative of activated mitophagy. Proteomic analysis corroborated these findings. This study demonstrates for the first time that Myr, a principal active component of RS polyphenols, exerts its therapeutic potential in DKD by inhibiting PIK3R1. This inhibition promotes XBP1 expression, indirectly activating both the PI3K/Akt and PINK1/Parkin pathways, ultimately enhancing autophagic flux.

Conclusions

Myr effectively activated autophagy and mitophagy by targeting the PI3K/Akt and PINK1/Parkin signaling pathways, facilitating the removal of dysfunctional mitochondria and mitigating cellular damage in DKD models. These findings provide a mechanistic foundation for the use of RS-derived polyphenols in chronic kidney disease management and highlight Myr's potential as a natural therapeutic agent for DKD.