Molecular Biology & Targeted Therapeutics | Ching-Hsien Chen Lab

We are excited to announce that our collaborative research team has received a new four-year, approximately $3 million NIH Multi-PI R01 grant to investigate how tobacco smoke drives fibrotic remodeling in the lung and to identify new therapeutic strategies for idiopathic pulmonary fibrosis (IPF).

IPF is a devastating and progressive interstitial lung disease characterized by irreversible scarring of the lungs and progressive loss of lung function. Tobacco smoking is an important environmental risk factor for IPF and is associated with more severe disease and poorer clinical outcomes. However, the molecular mechanisms connecting tobacco smoke exposure to persistent fibroblast activation and lung fibrosis remain poorly understood.

Our preliminary studies have uncovered a novel connection among cellular metabolism, protein post-translational modification, and fibrogenic signaling. Using proteomic and metabolomic approaches, we found that tobacco smoke promotes lactate accumulation and extensive protein lactylation in lung fibroblasts. Among these proteins, protein arginine methyltransferase 5 (PRMT5) emerged as a prominent non-histone target of lactylation. Our findings suggest that smoke-induced PRMT5 lactylation may increase PRMT5 stability and activity, thereby promoting fibroblast proliferation, invasion, and fibrogenic remodeling.

The new project will investigate how tobacco smoke-induced PRMT5 lactylation regulates fibroblast activation and determine how PRMT5 coordinates histone and non-histone methylation to drive profibrotic signaling. We will also evaluate whether pharmacological inhibition of PRMT5 can attenuate smoke-driven pulmonary fibrosis in preclinical models.

By connecting environmental tobacco exposure with metabolic reprogramming, protein lactylation, epigenetic regulation, and fibroblast activation, this research could reveal an entirely new mechanism underlying smoking-associated pulmonary fibrosis. Importantly, the project will determine whether PRMT5 represents a therapeutically actionable vulnerability that could ultimately lead to new treatment strategies for patients with IPF and other forms of progressive pulmonary fibrosis.

We are grateful for the NIH’s support of this collaborative research and look forward to advancing our understanding of the mechanisms that drive pulmonary fibrosis.

View Project on NIH RePORTER

We are excited to announce that our laboratory has received a four-year, approximately $2.5 million renewal of our NIH R01 grant from the National Heart, Lung, and Blood Institute (NHLBI) to continue our research on the mechanisms underlying tobacco smoke-driven pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive interstitial lung disease characterized by irreversible scarring of the lungs, progressive loss of lung function, and poor survival. Although tobacco smoking is an important environmental risk factor associated with IPF, the molecular mechanisms linking smoke exposure to the development and progression of lung fibrosis remain poorly understood.

Our renewed project, “Novel Role of Phospho-MARCKS in Macrophages During Tobacco Smoke-Driven Fibrosis,” will investigate how tobacco smoke reprograms macrophages toward a profibrotic state. Our studies have identified phosphorylated MARCKS (phospho-MARCKS) as a key smoke-responsive signaling molecule that may connect endoplasmic reticulum stress with chromatin remodeling and profibrotic gene expression in macrophages.

The project will define the molecular mechanisms by which phospho-MARCKS regulates macrophage polarization and determine whether targeting this pathway can attenuate smoke-driven lung fibrosis. We will combine mechanistic studies with macrophage-specific genetic models, pharmacological targeting, precision-cut lung slices (PCLS), and patient-derived autologous PCLS–immune cell co-culture models.

By uncovering how environmental exposure, cellular stress, epigenetic regulation, and macrophage dysfunction converge during fibrosis, this research aims to deepen our understanding of IPF pathogenesis and establish the MARCKS pathway as a potential therapeutic target. Ultimately, these studies may contribute to the development of new macrophage-targeted strategies for patients with IPF, particularly those with a history of tobacco smoke exposure.

We are grateful to the NIH/NHLBI for their continued support of our research and look forward to advancing our understanding of pulmonary fibrosis over the next four years.

View Project on NIH RePORTER