Targeting AKAP13 RhoGEF activity ameliorates pro-fibrotic phenotypes driven by the IPF associated AKAP13 risk variant

Abstract

RationaleIdiopathic pulmonary fibrosis (IPF) is a progressive, incurable scarring disease of the lung. A common genetic variant near AKAP13, a multifunctional scaffold protein that integrates intracellular signalling through its interactions with RhoA and protein kinase A (PKA), has been associated with IPF susceptibility and elevated AKAP13 mRNA expression in lung tissue from patients. However, its contribution to the pathogenesis of IPF remains unclear. ObjectiveThis study investigates how an AKAP13 variant alters epithelial signalling and evaluates the therapeutic potential of targeting AKAP13. Findingsrs62025270-bearing iHBECs exhibited selective upregulation of AKAP13 isoforms, accompanied by increased cell adhesion and reduced proliferation. Transcriptomic profiling revealed upregulated fibrosis-related genes in rs62025270-bearing iHBECs, including SAA1, FGF2, MMP1, CTSB, COL4A1, and CDKN1A. rs62025270-bearing iHBECs also displayed increased RhoA activation and SMAD2 phosphorylation following LPA stimulation. Furthermore, cells harbouring the AKAP13 variant showed reduced intracellular cAMP levels. Pharmacological inhibition of AKAP13 with A13 reversed the pro-adhesive phenotype and reduced RhoA activation in iHBECs. Moreover, in IPF-derived PCLS, A13 suppressed SERPINE1, CCN2, and MMP7 expression, reduced SMAD2 nuclear translocation, and decreased hydroxyproline levels. ConclusionsPresence of an AKAP13 variant disrupts epithelial homeostasis and promotes pro-fibrotic signalling. Inhibition of AKAP13s RhoGEF domain with A13 restores epithelial function and attenuates fibrotic activation, supporting AKAP13 as a therapeutic target in IPF.