SLC3A2-mediated BCAAs transport promotes airway inflammation and remodeling in chronic obstructive pulmonary disease via acetylation of PFN1.

INTRODUCTION

Chronic obstructive pulmonary disease (COPD) remains a leading cause of global burden, characterized by persistent airway inflammation and remodeling. Our previous study identified branched-chain amino acids (BCAAs) imbalance in patients with COPD, suggesting a potential contribution of metabolic reprogramming to the disease process. Solute carrier family 3 member 2 (SLC3A2), a key transporter for BCAAs uptake, plays a crucial role in amino acid homeostasis, yet its function in COPD pathogenesis remains unknown. This gap highlights the need to investigate whether SLC3A2-mediated BCAAs transport contributes to COPD.

OBJECTIVES

Building on our prior findings, this study aims to investigate the role of SLC3A2 in COPD-associated airway inflammation and remodeling, along with its regulatory mechanisms.

METHODS

SLC3A2 expression and BCAAs levels were quantified in clinical specimens and cigarette smoke (CS)-exposed animal and cellular models. The functional impact of SLC3A2 was assessed using lung function tests and histopathology in mice with airway epithelium-specific Slc3a2 knockout. In human bronchial epithelial (HBE) cells, SLC3A2 was modulated via knockdown or overexpression to elucidate its role in inflammation and remodeling. Immunoprecipitation assays were employed to identify regulators of SLC3A2 expression.

RESULTS

BCAAs disturbance and SLC3A2 upregulation were identified in COPD participants and CS-exposed mice, especially in airway epithelial cells. Airway epithelium-specific Slc3a2 knockout in mice alleviated BCAAs imbalance, airway inflammation and remodeling caused by CS. Mechanistically, SLC3A2-mediated BCAAs influx into epithelial cells enhanced acetyl coenzyme A production and profilin1 (PFN1) acetylation, activating the PI3K/AKT signaling axis and exacerbating inflammatory and remodeling responses. Notably, SLC3A2 upregulation was driven by CS-induced downregulation of HECT domain E3 ubiquitin protein ligase 4 (HECTD4).

CONCLUSION

This study elucidates the effects of SLC3A2-regulated BCAAs transport on airway inflammation and remodeling in COPD. Targeting SLC3A2 is a potential therapeutic approach for BCAAs imbalance and subsequent progression of COPD.