MICA-129Met/Val as a therapeutic compass in idiopathic pulmonary fibrosis: prognosis and antifibrotic benefit

Background – Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by aberrant wound healing, immune dysregulation, heterogeneous trajectories, and poor prognosis. Only two antifibrotic agents, nintedanib and pirfenidone, are currently approved to slow disease progression, yet inter-individual variability in treatment benefit remains largely unexplained. In IPF, impaired NK-cell activity within the altered lung microenvironment may hinder removal of stressed or senescent cells, promoting fibrosis. The MHC-class I chain-related gene A (MICA) encodes a stress-induced ligand of the NKG2D receptor on NK and CD8+ T cells, crucial for immune surveillance. Methods – We analyzed clinical and genetic data from 129 Sardinian IPF patients genotyped for MICA and stratified by antifibrotic therapy (nintedanib, pirfenidone, no therapy, and switchers). Genotypes were assessed in relation to longitudinal lung function, overall survival (OS), and treatment-specific outcomes using multivariate Cox models adjusted for demographic and immunogenetic variables. Results – MICA-129 genotype frequencies were comparable across treatment groups. In nintedanib-treated patients, the Val/Val genotype was associated with significantly reduced 48-month OS versus Met/Met and Met/Val (p = 0.005). No statistically significant association was observed among pirfenidone-treated patients. After adjustment, Val/Val remained an independent predictor of mortality in the nintedanib group (p = 0.01), irrespective of HLA background. Conclusions – The MICA-129 Val/Val genotype may represent a candidate immunogenetic marker associated with poorer outcome in nintedanib-treated patients with IPF, underscoring the influence of immune-genetic context on antifibrotic response. Although subgroup sizes limit precision, the consistency and mechanistic plausibility of the association support integrating MICA genotyping into future randomized trials to refine personalized therapeutic strategies in IPF.