Objective <p>Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by fibroblast activation and extracellular matrix deposition. Although mechanical forces are known to influence critical processes such as tissue remodeling and cellular differentiation, the specific role of mechanosensitive genes in IPF pathogenesis remains poorly understood.</p> Methods <p>This study applied mechanical force–related scoring to IPF and control samples. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify IPF-specific genes associated with mechanical force–related scores, which were subsequently subjected to enrichment analysis. Core genes were screened through univariate Cox regression analysis and machine learning algorithms. Independent prognostic genes were determined using stepwise multivariate Cox regression analysis, which informed the construction of a nomogram integrating key clinicopathological variables. The core genes were further analyzed through single-cell RNA sequencing (scRNA-seq) and Connectivity Map (CMap) analyses to investigate molecular subtypes and identify potential therapeutic targets.</p> Results <p>IPF samples exhibited significantly higher scores related to mechanical-related genes (MRGs). Moreover, these samples demonstrated notable heterogeneity, with distinct patterns of high and low mechanical force–associated scores. Core gene analysis revealed two distinct molecular subtypes among idiopathic IPF samples. The C2 subtype was characterized by pronounced inflammatory responses, activation of mechanotransduction pathways, and more severe pathological features. CMap analysis identified nifekalant, which targets AGTR2, as a potential therapeutic agent for the C2 subtype. CD24, PPP1R14C, DSP, and CC2D2A were identified as diagnostic biomarkers, among which CD24, PPP1R14C, and CC2D2A also served as independent prognostic indicators. scRNA-seq demonstrated elevated expression of CD24 and CC2D2A in IPF samples, predominantly within ciliated cells. Pseudotime trajectory analysis revealed two distinct cell fate trajectories in IPF samples. Differentiation toward cell fate 1 was associated with enhanced protein synthesis and secretion, whereas cell fate 2 and the branching point origin region exhibited increased cell adhesion and activation of the p38 MAPK signaling pathway.</p> Conclusion <p>CD24, PPP1R14C, and CC2D2A were identified as prognostic genes associated with MRGs, functioning as markers for molecular subtyping in IPF. These genes may contribute to the pathogenesis of IPF by modulating mechanotransduction processes within epithelial cell subpopulations.</p> Graphical Abstract <p></p>