Network medicine modeling of the m⁶A regulatory landscape identifies a KLF6–WTAP axis as a therapeutic target in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is sustained by multicellular circuits linking endothelial activation, fibroblast remodeling, and immune crosstalk. However, how N⁶-methyladenosine (m⁶A) regulation is embedded within these networks and how such network-level regulators can be prioritized as actionable nodes relevant to clinical pharmacology and safety remains unclear. Guided by a computational modelling and network medicine framework, we integrated single-cell RNA-seq with spatial transcriptomics to systematically profile 23 canonical m⁶A regulators in pulmonary fibrosis and to map their coupling to immune, cytokine, and extracellular-matrix (ECM) programs. CellChat-based ligand–receptor inference was used to reconstruct intercellular communication, while hdWGCNA co-expression modules and pseudotime trajectories resolved intracellular program architecture and dynamic transitions. Key nodes were further interrogated experimentally. WTAP function was evaluated via shRNA-mediated silencing in primary human lung fibroblasts and fibroblast-specific conditional deletion in a bleomycin (BLM)–induced mouse fibrosis model. Immunofluorescence, MeRIP-qPCR, ChIP-qPCR, luciferase reporter assays, RT-qPCR, and western blotting were used to validate WTAP expression, upstream regulation, and downstream m⁶A-linked effects. Network modelling highlighted IGF2BP3-associated sprouting angiogenesis with strengthened adhesion/chemokine signaling in endothelial cells and identified HNRNPA2B1 as a marker of pro-inflammatory macrophage states characterized by enhanced MDK and ITGB2 axes. In fibroblasts, WTAP emerged as a central m⁶A writer connecting an ECM/contractile module to a metabolic-to-mechanical transition along pseudotime. Spatial mapping and immunofluorescence confirmed elevated WTAP in fibroblast-enriched fibrotic regions. Functionally, WTAP silencing attenuated TGF-β–induced α-SMA and collagen III expression, reduced proliferation/migration, and lowered global m⁶A levels. Mechanistically, ChIP-qPCR and promoter reporter assays supported KLF6-dependent transcriptional activation of WTAP, and WTAP was associated with methylation-linked regulation of MYC, NR4A3, and IGFBP5. In vivo, fibroblast-specific WTAP deletion improved survival, preserved lung mechanics, and diminished collagen burden in BLM-treated mice. This study establishes a multi-omics network medicine map of m⁶A regulation in IPF and nominates the KLF6–WTAP axis as a central, potentially targetable hub coordinating pathogenic stromal programs. The framework provides a systems-level basis for target prioritization and for evaluating fibrosis-related safety liabilities and pharmacovigilance signals in clinical pharmacology.