Methylated circPTK2 as a driver of fibroblast activation in pulmonary fibrosis.

Pulmonary fibrosis (PF) is a life-threatening disease characterized by persistent fibroblast activation and excessive extracellular matrix deposition, leading to irreversible lung scarring and respiratory failure. Although epigenetic regulation has been increasingly implicated in PF, the contribution of RNA modifications, particularly N6-methyladenosine (m6A), remains poorly understood. In this study, we identify circPTK2, a fibroblast-specific circular RNA that is significantly upregulated in PF patients and experimental models. We demonstrate that its m6A-modified form (circPTK2-m(+)), but not the unmethylated isoform (circPTK2-m(-)) or its linear parental transcript, acts as a critical driver of fibroblast activation during PF progression. Silencing circPTK2-m(+) or disrupting its m6A methylation effectively attenuates fibroblast activation and alleviates fibrosis in vitro and in vivo. Mechanistically, elevated m6A writer METTL3 and reader RBMX cooperatively promote the alternative splicing of methylated PTK2 pre-mRNA to generate circPTK2-m(+), while another m6A reader EIF4A3 facilitates its nuclear export. In the cytoplasm, circPTK2-m(+) functions as a competing endogenous RNA, sequestering miR-484 and miR-125a-3p to relieve repression of YAP1 and FYN, thereby synergistically enhancing STAT3 activation and promoting a profibrotic transcriptional program. Collectively, these findings reveal a previously unrecognized role of m6A modification in PF pathogenesis and establish circPTK2-m(+) as a promising therapeutic target for PF intervention.