Nerandomilast's Antifibrotic Effects Are Modulated by the tRF-AKAP12-PKA Axis in Pulmonary Fibrosis

Pulmonary fibrosis (PF) involves persistent fibroblast activation, extracellular matrix deposition, and tissue stiffening. The role of oxidatively modified tRNA-derived small RNAs (tsRNAs) in linking fibroblast activation to mechanotransduction remains unclear.

5o8G tRF-1-AspGTC (tRF) expression was analyzed in lung tissues from patients with PF and experimental mouse models. Gain- and loss-of-function approaches were used to define its role in fibroblast activation and PF progression. Mechanistic studies examined the tRF-AKAP12-PKA-YAP pathway, and therapeutic relevance was evaluated by assessing the antifibrotic efficacy of Nerandomilast under AKAP12-deficient or AKAP12-restored conditions.

tRF was markedly upregulated in fibrotic lung tissues from PF patients and experimental mice. Myofibroblast-specific inhibition of this tRF significantly attenuated PF in mice. Consistently, tRF accumulation promoted fibroblast activation, cytoskeletal remodeling, and profibrotic phenotypes in human pulmonary fibroblasts (HPFs). Mechanistically, tRF directly targeted and suppressed AKAP12 expression, thereby disrupting the AKAP12-PKA signaling complex. Loss of AKAP12 disrupted AKAP12-dependent PKA compartmentalization, altered PKA substrate phosphorylation, and promoted cytoskeletal reorganization and YAP-dependent mechanotransduction. Importantly, AKAP12 deficiency impaired Nerandomilast-mediated restoration of PKA-YAP signaling and limited its antifibrotic efficacy, whereas AKAP12 restoration re-established this signaling axis and synergistically enhanced Nerandomilast therapeutic effects in PF mice.

tRF promotes PF by disrupting AKAP12-dependent spatial PKA signaling and activating YAP-dependent mechanotransduction. Targeting the tRF-AKAP12 axis, particularly through AKAP12 restoration, may improve Nerandomilast-based therapy.