Luteolin attenuates RA-associated chronic pain by targeting the LDHA/H3K9la/NFATC2 axis to suppress Th17 cell differentiation and central infiltration
Yuepeng Jiang, Yang Zhao, Xiao Ma, Xiaoxuan Zhao, Mengjia Zheng, Junjun Wen, Cun-Rui Yuan, Xinyi Ding, Chengping Wen
Abstract
Chronic joint pain in rheumatoid arthritis (RA) represents a persistent therapeutic challenge, and although luteolin (LUT) exhibits established anti-inflammatory properties, its precise mechanism for alleviating RA-associated chronic pain remains undefined. Through systematic investigation in collagen-induced arthritis (CIA) mice, we demonstrated that LUT administration effectively attenuated chronic pain by modulating spinal cluster of differentiation 4 positive T (CD4 + T) cell dynamics and suppressing microglial activation. Integrated multi-omics profiling (cleavage under targets and tagmentation, RNA sequencing (RNA-seq), and metabolomics) coupled with functional validation revealed nuclear factor of activated T cells 2 (NFATC2) as the central transcriptional regulator governing T helper 17 (Th17) cell differentiation and spinal infiltration through protein kinase C epsilon (PRKCE)-signal transducer and activator of transcription 3 (STAT3) signaling transduction. Significantly, our mechanistic studies uncovered a previously unrecognized epigenetic cascade: LUT-mediated suppression of lactate dehydrogenase A (LDHA) activity disrupts glycolysis-fueled histone h3 lysine 9 lactylation (H3K9la), thereby epigenetically silencing NFATC2 transcription. Translational studies using RA patient-derived CD4 + T cells confirmed LUT's capacity to normalize pathological hyperactivity of the LDHA/H3K9la/NFATC2 axis, concomitantly regulating CD4 + T dynamics. Biophysical validation through molecular docking, surface plasmon resonance, and molecular dynamics simulations established LUT's direct binding to LDHA with high affinity. Collectively, these findings delineate a novel therapeutic paradigm wherein LUT alleviates RA-associated chronic pain by orchestrating Th17 differentiation and migratory capacity through coordinated blockade of the LDHA-H3K9la-NFATC2 signaling network, highlighting its potential as a disease-modifying agent for chronic pain management in RA.