Idiopathic pulmonary fibrosis (IPF), representing one of the most aggressive types of pulmonary fibrosis (PF), is characterized by progressive and irreversible lung scarring that leads to respiratory failure and high mortality [1,2]. This devastating disease is likely the result of a complex interplay between genetic predisposition and environmental triggers [3]. Currently, both pirfenidone and nintedanib serve as frontline treatment options for IPF, but their clinical utility is significantly constrained by substantial treatment costs and notable side effects, thereby limiting long-term patient adherence [4]. Consequently, developing novel therapeutic agents that are safer, more cost-effective, and more efficacious has become a key focus of research.

Emerging evidence highlights galectin-3 (LGALS3) as a critical regulator of PF, with marked upregulation observed in IPF [5]. LGALS3 is involved in multiple pathological processes such as cell adhesion and proliferation [6,7], while its downregulation has been shown to inhibit myofibroblast activation and procollagen (I) expression [8]. Therefore, targeting and regulating LGALS3 may provide potential support for IPF treatment. 2,3,5,6-tetrafluoro-4-methoxybenzamide (TFMB), a synthetic small molecule with regulatory potential [9], has been found to have an inhibitory effect on LGALS3 in humans [10,11]. Moreover, preclinical evidence has shown that LGALS3 inhibition is capable of alleviating IPF in murine models [12]. This suggests that TFMB may be a promising candidate for IPF treatment through LGALS3 modulation.

Advanced glycation end products (AGEs) are closely related to the onset of various diseases [13]. It has been reported that AGE-receptor for AGE (RAGE) signaling reduces extracellular matrix (ECM) buildup by inhibiting epithelial-mesenchymal transition (EMT) in rat alveolar epithelial cells through SMAD7 activation [14]. Regardless of the initial clinical manifestations or histological features, IPF is invariably accompanied by abnormal ECM remodeling, which is primarily mediated by pulmonary fibroblasts and myofibroblasts that play a central role in fibrosis [15]. This pathological process is further exacerbated by ongoing aging-related alveolar epithelial micro-damage that disrupts epithelial-fibroblast communication, which in turn triggers myofibroblast recruitment and activation, leading to collagen-rich ECM production [4,16]. Notably, LGALS3, as a high-affinity AGE-binding protein, can act as an alternative receptor for AGEs [17,18]. On this basis, we hypothesize that TFMB may alleviate IPF by inhibiting LGALS3, thereby relieving its inhibitory effect on AGE-RAGE pathway activation, which contributes to the attenuation of pulmonary fibrosis.

Although TFMB's pharmacological activity in suppressing LGALS3 has been mechanistically linked to IPF attenuation, the precise molecular mechanism by which TFMB regulates LGALS3 expression to mitigate IPF has not been studied. To address this knowledge gap, we constructed both mouse and lung fibroblast models of IPF, and systematically explored TFMB's anti-fibrotic effects in IPF employing LGALS3 and RAGE overexpression interventions.