Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by persistent fibroblast activation, metabolic dysregulation, and redox imbalance. Retinoic acid (RA), a bioactive metabolite of vitamin A, is critical for tissue repair and homeostasis; however, its precise role in fibrotic lung remodeling remains poorly understood. This study aimed to define the metabolic rewiring of the RA pathway in fibrotic lungs and to determine whether modulating RA metabolism confers antifibrotic benefits. Methods We integrated multi-omics profiling with multimodal functional analyses to investigate RA metabolic remodeling in pulmonary fibrosis. Transcriptomic and spatial metabolomic analyses were performed on human fibrotic lungs and bleomycin (BLM)-induced mouse models. Mechanistic studies in primary fibroblasts and genetically engineered mice were used to elucidate the impact of CYP26A1/CYP26B1 inhibition or deletion and dietary vitamin A supplementation on RA signaling, fibroblast activation, and fibrogenesis. Results Transcriptomic analyses revealed pronounced reprogramming of retinoid metabolism in fibrotic lungs, particularly within disease-driving fibroblasts. These cells selectively upregulate the RA-catabolizing enzymes CYP26A1 and CYP26B1, thereby effectively silencing RA signaling. Spatial metabolomics confirmed severe depletion of RA and retinyl esters (RE) in fibrotic lesions from both patients and BLM-treated mice. Mechanistically, RA formed a transcriptional complex with RAR-RXR, activating an NRF2-dependent antioxidant program that suppressed TGF-β signaling and fibroblast senescence. Genetic or pharmacological inhibition of CYP26A1/CYP26B1 restored RA signaling, mitigated redox-dependent fibroblast activation and extracellular matrix production, and attenuated BLM-induced fibrosis. Notably, chronic dietary vitamin A supplementation replenished endogenous RE stores, improved lung function and survival, and exhibited superior antifibrotic efficacy compared with retinol or RA administration. Conclusions Our study identifies RA metabolic rewiring as a central mechanism driving fibroblast activation and disease progression in IPF. Targeting RA catabolism through CYP26A1/CYP26B1 inhibition or dietary modulation restores endogenous RA signaling and alleviates fibrosis, highlighting a promising therapeutic avenue for antifibrotic intervention. This abstract is funded by: National Natural Science Foundation of China (8240010395), Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0529000 & 2023ZD0516900), Shanghai Municipal Health Commission (2023ZZ02025), The National Key Research and Development Program of China (2024YFC3044600), Science and Technology Commission of Shanghai Municipality (24YF2735300), Tongji University Medicine-X Interdisciplinary Research Initiative (2025-0554- YB-02).
Tang et al. (Fri,) studied this question.