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Rhizopus and Mucor are the most common etiological agents, with rhino-orbital-cerebral mucormycosis being the most frequent form of the disease. In this study, we sought to determine the activation of apoptosis, necroptosis, ferroptosis, and pyroptosis along with oxidative stress markers, in formalin-fixed paraffin embedded rhino-orbital tissues from patients with mucormycosis and COVID-19-Associated-Mucormycosis (CAM). We observed increased expression of 3-nitrotyrosine and phosphorylated Nuclear factor Erythroid 2-related factor 2, suggesting the presence of oxidative stress in these tissues. Elevated levels of CD71, phosphorylated MLKL (Mixed lineage kinase domain-like protein), and cleaved caspase 3 were detected in both mucormycosis and CAM tissues, indicating differential activation of ferroptosis, necroptosis and apoptosis during fungal infection. Notably, cleaved gasdermin D was not detected, indicating that pyroptosis does not play a significant role in mediating host lytic cell death during invasive mucormycosis. Our findings, which identify differential activation of programmed cell death pathways directly in human tissues, meet an important critical gap in the mucormycosis literature and highlight viable targets for future therapeutic interventions.<\/jats:p>","DOI":"10.1093\/mmy\/myaf104","type":"journal-article","created":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T07:05:15Z","timestamp":1762671915000},"source":"Crossref","is-referenced-by-count":1,"title":["Immunohistochemical insights into oxidative stress and programmed cell death in primary and COVID-associated rhino-orbital-cerebral mucormycosis patient tissues"],"prefix":"10.1093","volume":"63","author":[{"given":"Srijita","family":"Kundu","sequence":"first","affiliation":[{"name":"Prof. Brien Holden Eye Research Centre, LV Prasad Eye Institute , Hyderabad-500034 ,","place":["India"]},{"name":"Graduate Studies, Manipal Academy of Higher Education , Manipal-576104 ,","place":["India"]},{"name":"Dr. Chigurupati Nageswara Rao Ocular Pharmacology Research Centre, LV Prasad Eye Institute , Hyderabad-500034 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashleigh N","family":"Riegler","sequence":"additional","affiliation":[{"name":"The University of Alabama at Birmingham Division of Laboratory Medicine, Department of Pathology, , Birmingham, AL-35294 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajeshwari","family":"Chelappan","sequence":"additional","affiliation":[{"name":"The University of Alabama at Birmingham Division of Laboratory Medicine, Department of Pathology, , Birmingham, AL-35294 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilip K","family":"Mishra","sequence":"additional","affiliation":[{"name":"Ophthalmic Pathology Laboratory, LV Prasad Eye Institute , Hyderabad-500034 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarjani V","family":"Dave","sequence":"additional","affiliation":[{"name":"Ophthalmic Plastic Surgery Service, LV Prasad Eye Institute , Hyderabad-500034 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6939-9572","authenticated-orcid":false,"suffix":"Jr","given":"Sixto M","family":"Leal","sequence":"additional","affiliation":[{"name":"The University of Alabama at Birmingham Division of Laboratory Medicine, Department of Pathology, , Birmingham, AL-35294 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0407-8177","authenticated-orcid":false,"given":"Sanhita","family":"Roy","sequence":"additional","affiliation":[{"name":"Prof. Brien Holden Eye Research Centre, LV Prasad Eye Institute , Hyderabad-500034 ,","place":["India"]},{"name":"Dr. Chigurupati Nageswara Rao Ocular Pharmacology Research Centre, LV Prasad Eye Institute , Hyderabad-500034 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