NEAT1 drives SARS-CoV-2 N protein–induced inflammation, metabolic reprogramming, and mitochondria–ER stress crosstalk

SARS-CoV-2 remains a global health concern. Although its nucleocapsid (N) protein supports viral replication and evades host immunity, its role in host metabolic reprogramming and organelle homeostasis is not fully understood. This study aims to elucidate whether the N protein modulates glycolysis and mitochondrial-ER stress crosstalk via the long non-coding RNA NEAT1. We established human bronchial epithelial (HBE) cells stably expressing the N protein. Inflammatory and glycolytic gene expression was analyzed by qRT-PCR and Western blot. ROS levels were measured by flow cytometry, while mitochondrial membrane potential, Ca²⁺ overload, and mitochondria-ER contact sites (MAMs) were assessed by confocal microscopy. NEAT1 knockdown and HK2-VDAC1 interaction studies were performed to explore underlying mechanisms. The N protein induced inflammatory responses, enhanced LPS sensitivity, and triggered mitochondrial dysfunction, ER stress, and MAM formation. It promoted glycolytic reprogramming by upregulating key enzymes (GLUT1, HK2, PKM2). NEAT1 was essential for these effects-N protein increased NEAT1 expression, and NEAT1 knockdown attenuated inflammation, glycolysis, and mitochondrial damage. Mechanistically, NEAT1 silencing restored HK2-VDAC1 association and suppressed VDAC1 oligomerization. The SARS-CoV-2 N protein exacerbates inflammation through a NEAT1-dependent mechanism that drives glycolytic reprogramming and disrupts mitochondrial-ER homeostasis.