Abstract Objective Pulmonary hypertension (PH) frequently complicates pulmonary fibrosis (PF) and is significantly associated with worse cardiopulmonary function and survival. A major unment need is the absence of therapies that can simultaneously attenuate both pulmonary parenchymal fibrotic remodeling and pulmonary vascular remodeling. Fibroblast activation and proliferation contributes not only to interstitial fibrosis but also to adventitial thickening of distal pulmonary arteris, reduced pulmonary and vascular compliance. Our previous work suggested that dysregulated DNA damage response is a shared mechanism underlying these two pathophysiological processes. Translationally controlled tumor protein (TCTP) has been implicated in the maintenance of genomic stability and in the modulating cellular responses to DNA damage, may therefore be a convergent target in PF associated PH (PF-PH). Methods Lung tissue samples from patients with PF-PH and healthy controls were assessed for fibrosis severity by Masson’s trichrome staining and for TCTP expression by Western Blot. A bleomycin-induced PF mouse model were established to evaluate TCTP protein expression and cellular localization in vivo. In vitro, primary human lung fibroblasts were stimulated by TGF-β1 in the presence or absence of TCTP inhibitors, then TCTP expression, fibroblast proliferation and myofibroblast activation were examined by Western blot and immunofluorescence. Additionally, TCTP knockdown using siRNA (siTCTP) were performed to validate TCTP-dependent effect on TGF-β1-induced phenotypic changes. Results Western blot analysis confirmed elevated TCTP protein expression in lung tissues, distal pulmonary arteries, and lung fibroblasts of patients with PF (n = 10) and PF-PH (n = 7) Compared to normal controls (n = 7). This elevation showed positive correlations with the degree of pulmonary fibrosis (r² = 0.41, P = 0.001) and pulmonary arterial remodeling (r² = 0.38, P = 0.015). Similarly, significantly increased TCTP protein levels were observed in lung tissues of bleomycin-induced PF mice. In vitro, TGF-β1 stimulation markedly upregulated TCTP expression in fibroblasts (confirmed by western blot and immunofluorescence). Both pharmacological inhibition and genetic knockdown of TCTP significantly suppressed TGF-β1-induced proliferation (confirmed by western blot of PCNA and Survivin) and myofibroblast differentiation (confirmedby western blot of ɑ-SMA, fibronectin and collagen I) in human lung fibroblasts. Conclusion This study reveals that TCTP expression is elevated in PF and PF-PH. Inhibiting TCTP expression can attenuate the activation and proliferation of lung fibroblasts, as well as collagen deposition. Further investigation is warranted to elucidate the role of TCTP in the pathogenesis of PF-PH and its therapeutic potential for PF-PH. This abstract is funded by: This work was supported by the Program of National Key Research and Development projects of China (2023YFC2509500) and the Program of National Natural Science Foundation of China (82570413), the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0526700, 2024ZD0528600), the the Pujiang Talent Program (22OHD064), and the Program of Shanghai Pulmonary Hospital (2025-0554-YB-15, LYRC202415).
Feng et al. (Fri,) studied this question.