The value of macrolides in the adjuvant treatment of pulmonary fibrosis: maybe a panacea.

Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease characterized by excessive extracellular matrix deposition and fibroblast activation. Current antifibrotic therapies, such as nintedanib and pirfenidone, slow disease progression but fail to halt fibrosis or significantly improve survival. Macrolides, a class of antibiotics with immunomodulatory and anti-inflammatory properties, have emerged as potential adjunctive therapies for PF. Preclinical studies demonstrate that macrolides attenuate fibrogenesis through multifaceted mechanisms: suppression of TGF-β/Smad and JNK/c-Jun signaling, inhibition of pro-fibrotic cytokine release, modulation of macrophage polarization toward antifibrotic M2 phenotypes, and induction of apoptosis in senescent cells. Clinically, macrolides have shown promise in reducing acute exacerbations in idiopathic pulmonary fibrosis (IPF), mitigating radiation pneumonitis, and attenuating post-infectious fibrotic changes. However, conflicting results from clinical trials and the absence of large-scale randomized studies highlight the need for further validation. This review evaluates the antifibrotic mechanisms and therapeutic potential of macrolides in PF, integrating preclinical and clinical evidence. We aim to inform future research directions by elucidating their role in modulating key pathways and addressing unresolved efficacy questions.