Effects of the WNT signaling pathway on inflammation and fibrosis in idiopathic pulmonary fibrosis: Clinical, radiological and molecular evaluation

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by irreversible fibrosis, radiological honeycombing and a progressive decline in pulmonary function. Although antifibrotic agents such as pirfenidone and nintedanib can slow disease progression, these agents fail to reverse established structural damage, underscoring the urgent need for novel therapeutic strategies. Notably, the WNT signaling pathway has been implicated in fibrogenesis, suggesting it may represent a promising therapeutic target in IPF. The present study aimed to elucidate the role of WNT signaling in IPF pathogenesis, and to evaluate the antifibrotic and anti‑inflammatory effects of the WNT inhibitors ETC‑159 and LGK‑974 in vitro. A prospective case‑control study was conducted, including 33 patients with IPF and 23 healthy controls. WNT gene expression in peripheral blood was quantified using quantitative PCR. Fibrotic markers [α‑smooth muscle actin (α‑SMA) and collagen type I] and inflammatory cytokines (IL‑1β, IL‑6 and TGF‑β2) were measured by ELISA. Additionally, LL29 (AnHa) fibroblasts from a patient with IPF were treated with ETC‑159 or LGK‑974 to assess molecular and phenotypic responses. Patients with IPF exhibited significant upregulation of WNT‑2, WNT‑4, WNT‑6, WNT‑7a/b and WNT‑10a/b, whereas WNT‑1 and WNT‑3a showed no significant change. Collagen type I and α‑SMA levels were also markedly elevated in IPF. Treatment with LGK‑974 significantly reduced both α‑SMA and collagen type I expression, whereas ETC‑159 selectively decreased collagen type I. Both inhibitors suppressed IL‑6, whereas LGK‑974 additionally reduced IL‑1β. In conclusion, aberrant activation of WNT signaling may contribute to fibrogenesis and inflammation in IPF. Pharmacological inhibition of this pathway, particularly with LGK‑974, exerts potent antifibrotic and anti‑inflammatory effects, highlighting WNT signaling as a viable therapeutic target for IPF.