Systems Integration of the SARS-CoV-2 ORF7b–c-Myc–PVT1–miR-145/214–HIF-2α–TFRC–CCL2 Axis in Long COVID Pathobiology and Epigenetic Reversal

Post-Acute Sequelae of SARS-CoV-2 (PASC), clinically designated as Long COVID, affects over 400 million individuals globally, presenting as a multisystem disorder characterized by chronic microvascular endotheliitis, exertional exhaustion, pathological cardiac remodeling, and systemic autoimmunity [1–3]. While acute COVID-19 is primarily initiated by viral entry via ACE2, persistent post-viral sequelae are driven by sustained expression of viral accessory factors and host transcriptional hijacking [1,2,4]. Here, we establish a comprehensive systems-biology framework demonstrating that SARS-CoV-2 accessory protein Orf7b overexpression drives high-amplitude transactivation of master oncogene c-Myc, which hypertranscribes long non-coding RNA PVT1 [1,2]. The resultant multi-isoform surge of PVT1 linear, circPVT1, and ecDNA transcripts acts as a high-capacity competing endogenous RNA (ceRNA) network that sequesters protective host microRNA-145-5p (miR-145-5p) and miR-214 [1,2]. This dual microRNA depletion initiates a secondary derepression cascade involving hypoxia-inducible factor-2α (HIF-2α / EPAS1) and Transferrin Receptor 1 (TFRC / TfR1) [1,2,4,5]. Dense TFRC accumulation accelerates diferric transferrin endocytosis, expanding the intracellular labile iron pool, driving ROS-dependent transcription and secretion of chemokine CCL2, and provoking concentric cardiac hypertrophy, microvascular endotheliitis, ACE2-independent viral entry, and TLR7-regulated TFR1-driven B-cell autoimmunity [1–6]. Crucially, we demonstrate that this entire pathological network can be reversed upstream by host-directed p53/NRF2-based epigenetic shielding via miR-145-5p transactivation, 3'-UTR transcript cleavage, and mitochondrial cristae restoration [1,2,7].