{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T02:58:03Z","timestamp":1790132283554,"version":"4.0.1"},"reference-count":45,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:00:00Z","timestamp":1768435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although the SARS-CoV-2 pandemic no longer poses a global emergency, the virus continues to diversify and acquire immunoevasive properties. Understanding the molecular pathways that shape SARS-CoV-2 pathogenesis has become essential. In this paper, we summarize the most recent current evidence on how the spike protein structurally evolves, on changes in key non-structural proteins, such as nsp14, and on host factors, such as TMPRSS2 and neuropilin-1. These changes, together, shape viral entry, replication fidelity and interferon antagonism. Given the emerging Omicron variants of SARS-CoV-2, recent articles in the literature, cryo-EM analyses, and artificial intelligence-assisted mutational modeling were analyzed to infer and contextualize mutation-driven mechanisms. It is through these changes that the virus adapts and evolves, such as optimizing angiotensin-converting enzyme binding, modifying antigenic surfaces, and accumulating mutations that affect CD8+ T-cell recognition. Multi-omics data studies further support SARS-CoV-2 pathogenesis through convergent evidence linking viral adaptation to host immune and metabolic reprogramming, as occurs in myocarditis, liver injury, and acute kidney injury. By integrating proteomic, transcriptomic, and structural findings, this work presents how the virus persists and dictates disease severity through interferon antagonism (ORF6, ORF9b, and nsp1), adaptive immune evasion, and metabolic rewiring. All these insights underscore the need for next-generation interventions that provide a multidimensional framework for understanding the evolution of SARS-CoV-2 and guiding future antiviral strategies.<\/jats:p>","DOI":"10.3390\/ijms27020891","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T16:21:13Z","timestamp":1768494073000},"page":"891","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Molecular Aspects of Viral Pathogenesis in Emerging SARS-CoV-2 Variants: Evolving Mechanisms of Infection and Host Response"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7066-7424","authenticated-orcid":false,"given":"Sofia Teodora","family":"Muntean","sequence":"first","affiliation":[{"name":"Doctoral School of Medicine and Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of T\u00e2rgu Mures, 540139 Targu Mures, Romania"},{"name":"Department of Pathophysiology, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of T\u00e2rgu Mures, 540139 Targu Mures, Romania"},{"name":"Pneumology Department, Clinical County Hospital of Mure\u0219, 540142 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea-Raluca","family":"Cozac-Szoke","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of T\u00e2rgu Mures, 540139 Targu Mures, Romania"},{"name":"Pathology Department, Clinical County Hospital of Mure\u0219, 540011 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9603-6256","authenticated-orcid":false,"given":"Andreea Ca\u0306ta\u0306lina","family":"Tinca","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of T\u00e2rgu Mures, 540139 Targu Mures, Romania"},{"name":"Pathology Department, Clinical County Hospital of Mure\u0219, 540011 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1172-8262","authenticated-orcid":false,"given":"Irina Bianca","family":"Kosovski","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of T\u00e2rgu Mures, 540139 Targu Mures, Romania"},{"name":"Clinical Laboratory Department, Clinical County Hospital of Mure\u0219, 540072 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silviu","family":"Vultur","sequence":"additional","affiliation":[{"name":"Plastic, Aesthetic and Reconstructive Microsurgery Department, County Emergency Clinical Hospital of T\u00e2rgu Mure\u0219, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Vultur","sequence":"additional","affiliation":[{"name":"Plastic, Aesthetic and Reconstructive Microsurgery Department, County Emergency Clinical Hospital of T\u00e2rgu Mure\u0219, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ovidiu Simion","family":"Cotoi","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of T\u00e2rgu Mures, 540139 Targu Mures, Romania"},{"name":"Pathology Department, Clinical County Hospital of Mure\u0219, 540011 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anca Ileana","family":"Sin","sequence":"additional","affiliation":[{"name":"Department of Genetics and Cellular and Molecular Biology, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of T\u00e2rgu Mures, 540139 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Budin, C.E., Neme\u0219, A.F., R\u00e2jnoveanu, R.-M., Neme\u0219, R.M., Rajnoveanu, A.G., Sab\u0103u, A.H., Cocuz, I.G., Mare\u0219, R.G., Oniga, V.I., and P\u0103tr\u00eenta\u0219u, D.E. 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