Qi Pan, Aiwei Zhou, Tianyi Yang, Tianyi Lin, Bingran Wang, Wanglong Xiao, Yunmu Gao, Jiaqi Song, Hongyuan Liu, Wanmei Zhou, Zitong Chen, Yingchun Yang, Qianxiao Cheng, Zhicong Zhao, Taihua Yang, Yuan Liu, Yongbo Liu, Qiang Xia
Pediatric liver transplantation is frequently complicated by T cell-mediated rejection (TCMR), yet graft-intrinsic regulators and actionable biomarkers remain limited. Using integrative RNA profiling and mechanistic interrogation, we identify circFADS2 (FADS2 exons 2-5) as a hepatocyte-dominant circular RNA that is markedly reduced in TCMR. circFADS2 distinguishes TCMR from non-rejection with an AUC of 0.86, supporting its potential as a candidate biopsy-based molecular adjunct to characterize rejection-associated graft remodeling. Mechanistically, circFADS2 binds P2RY1 mRNA and engages an HNRNPD-dependent decay program to promote transcript destabilization, reducing P2RY1 abundance and attenuating P2RY1-linked signaling output as assessed by diminished agonist-evoked Ca2+ mobilization and reduced phosphorylation of downstream effectors including MNK1 and cPLA2. Consistent with this signaling attenuation, circFADS2 overexpression reduces arachidonic acid (AA) and AA-derived lipid mediators released from hepatocytes. Limiting AA is accompanied by reduced CD4+ T cell activation, proliferation, and effector cytokine production in hepatocyte-conditioned media assays. Finally, pharmacologic P2RY1 stimulation exacerbates, whereas P2RY1 inhibition alleviates, graft injury in a murine liver transplantation model, supporting the in vivo relevance of the P2RY1-linked pathway downstream of circFADS2.