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Abdullah R Alzahrani,1 Doaa I Mohamed,2 Hebatallah H Abo Nahas,3 Dalia Alaa El-Din Aly El-Waseef,4 Abdulmalik S Altamimi,5 Ibrahim H Youssef,6 Ibrahim Abdel Aziz Ibrahim,1 Soha MY Mohamed,7 Yasmine Gamal Sabry,7 Alaa H Falemban,1 Nasser Attia Elhawary,8 Ghazi A Bamagous,1 Mariusz Jaremko,9 Essa M Saied10,11 1Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia; 2Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 3Zoology Department, Faculty of Science, Port Said University, Port Said, Egypt; 4Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 5Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia; 6Department of Chest Diseases, Faculty of Medicine, Al-Azhar University, Cairo, Egypt; 7Physiology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 8Department of Medical Genetics, College of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia; 9Smart-Health Initiative and Red Sea Research Center, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia; 10Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, Egypt; 11Institute for Chemistry, Humboldt Universität Zu Berlin, Berlin, GermanyCorrespondence: Essa M Saied, Institute for Chemistry, Humboldt Universität zu Berlin, Berlin, 12489, Germany, Email saiedess@hu-berlin.deIntroduction: Pulmonary fibrosis (PF) and tissue remodeling can greatly impair pulmonary function and often lead to fatal outcomes.Methodology: In the present study, we explored a novel molecular interplay of long noncoding (Lnc) RNA CBR3-AS1/ miRNA-29/ FIZZ1 axis in moderating the inflammatory processes, immunological responses, and oxidative stress pathways in bleomycin (BLM)-induced lung fibrosis. Furthermore, we investigated the pharmacological potential of Trimetazidine (TMZ) in ameliorating lung fibrosis.Results: Our results revealed that the BLM-treated group exhibited a significant upregulation in the expression of epigenetic regulators, lncRNA CBR3-AS1 and FIZZ1, compared to the control group (P< 0.0001), along with the downregulation of miRNA-29 expression. Furthermore, Correlation analysis showed a significant positive association between lnc CBR3-AS1 and FIZZ1 (R=0.7723, p< 0.05) and a significant negative association between miRNA-29 and FIZZ1 (R=− 0.7535, p< 0.05), suggesting lnc CBR3-AS1 as an epigenetic regulator of FIZZ1 in lung fibrosis. BLM treatment significantly increased the expression of Notch, Jagged1, Smad3, TGFB1, and hydroxyproline. Interestingly, the administration of TMZ demonstrated the ability to attenuate the deterioration effects caused by BLM treatment, as indicated by biochemical and histological analyses. Our investigations revealed that the therapeutic potential of TMZ as an antifibrotic drug could be ascribed to its ability to directly target the epigenetic regulators lncRNA CBR3-AS1/ miRNA-29/ FIZZ1, which in turn resulted in the mitigation of lung fibrosis. Histological and immunohistochemical analyses further validated the potential antifibrotic effects of TMZ by mitigating the structural damage associated with fibrosis.Discussion: Taken together, our study showed for the first time the interplay between epigenetic lncRNAs CBR3-AS1 and miRNA-29 in lung fibrosis and demonstrated that FIZZ1 could be a downregulatory gene for lncRNA CBR3-AS1 and miRNA-29. Our key findings demonstrate that TMZ significantly reduces the expression of fibrotic, oxidative stress, immunomodulatory, and inflammatory markers, along with epigenetic regulators associated with lung fibrosis. This validates its potential as an effective antifibrotic agent by targeting the CBR3-AS1/miRNA-29/FIZZ1 axis. Keywords: lung fibrosis, long noncoding RNA CBR3-AS1, miRNA-29, FIZZ1, trimetazidine, histopathology