Knockdown of JMJD3 ameliorates cigarette smoke extract-triggered bronchial epithelial cell injury via ACSL4-dependent ferroptosis

Area of Science:

• Pulmonary Medicine
• Cell Biology
• Molecular Mechanisms of Disease

Background:

• Chronic obstructive pulmonary disease (COPD) is a major global health concern with high prevalence and mortality.
• Understanding the molecular pathways underlying COPD pathogenesis is crucial for developing effective treatments.
• Jumonji domain-containing protein-3 (JMJD3) has emerged as a potential regulator in inflammatory and cellular stress responses.

Purpose of the Study:

• To investigate the role of JMJD3 in cigarette smoke extract (CSE)-induced damage in human bronchial epithelial cells (BEAS-2B).
• To elucidate the underlying mechanisms, focusing on ferroptosis and its association with JMJD3 and ACSL4.
• To explore the therapeutic potential of targeting JMJD3 in COPD-related cellular injury.

Main Methods:

• Human bronchial epithelial cells (BEAS-2B) were exposed to cigarette smoke extract (CSE).
• JMJD3 was silenced, and acyl-CoA synthetase long-chain family member 4 (ACSL4) was overexpressed.
• Cell viability, cytotoxicity, oxidative stress, inflammation, lipid peroxidation, and ferroptosis markers were assessed using various assays (CCK-8, ELISA, DCFH-DA, BODIPY 581/591 C11, Western blot).

Main Results:

• CSE exposure increased JMJD3 expression in BEAS-2B cells.
• JMJD3 silencing improved cell viability, reduced inflammation, oxidative stress, and inhibited ferroptosis.
• JMJD3 depletion increased H3K27me3 and decreased ACSL4 expression, while ACSL4 overexpression reversed the protective effects of JMJD3 silencing.

Conclusions:

• JMJD3 plays a critical role in CSE-induced lung cell damage by promoting ferroptosis.
• JMJD3 depletion suppresses ferroptosis, potentially via regulating ACSL4 expression and H3K27me3 levels.
• Targeting JMJD3 may offer a novel therapeutic strategy to alleviate inflammation and oxidative stress in COPD.