Targeting microglial inflammation in Parkinson's disease: irisin activates PAFAH1B1-RAGE ubiquitination and TFEB-dependent autophagy to alleviate neurodegeneration.

Investigate irisin's therapeutic potential in Parkinson's disease (PD). Clinical data from 120 PD patients and 120 controls were analyzed. MPTP-induced PD mice and LPS-stimulated BV2 microglia models were used. In vivo, mice were divided into control, PD, and PD + Irisin groups for behavioral and histological assessments. In vitro, LPS-stimulated BV2 cells were treated with irisin or PBS. RNA sequencing, immunohistochemistry, and Western blot evaluated autophagy, inflammation, and ubiquitination pathways. PD patients exhibited increased TNF-α and IL-1β but decreased irisin levels. In PD mouse models, irisin improved motor deficits, increased nigrostriatal neuron numbers, restored tyrosine hydroxylase expression, and reduced α-synuclein aggregation. It also suppressed microglial inflammation and promoted anti-inflammatory polarization. Mechanistically, irisin enhanced autophagic flux, regulated RAGE ubiquitination mediated by PAFAH1B1, and inhibited neuroinflammation via the TFEB-NLRP3 axis. Specifically, PAFAH1B1 regulated RAGE expression through K61 and K169 sites on K48-linked polyubiquitin chains. Additionally, irisin restored lysosomal function by promoting TFEB nuclear translocation, enhancing NLRP3 inflammasome degradation, and reducing inflammatory factor secretion, thus alleviating neuroinflammation. Irisin alleviates PD pathology by modulating autophagy and ubiquitination pathways, suggesting its potential as a novel immunomodulatory target for PD.