{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T22:25:19Z","timestamp":1789683919710,"version":"4.0.1"},"reference-count":104,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Multiple myeloma profoundly remodels the bone marrow microenvironment, causing osteolytic bone disease through a persistent uncoupling of bone resorption and formation. Beyond the canonical roles of the receptor activator of nuclear factor kappa-B ligand\/receptor activator of nuclear factor kappa-B\/osteoprotegerin triad and Wnt antagonism, three interdependent stress programs orchestrate the osteolytic niche. These include oxidative stress driven by mitochondrial and nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species; sterile inflammation sustained by damage-associated molecular patterns, pattern-recognition receptors, and pro-inflammatory cytokines; and autophagy\u2013lysosomal remodeling governed by transcription factor EB and the coordinated lysosomal expression and regulation network. These axes intersect with iron handling and lipid peroxidation to regulate sensitivity to ferroptotic cell death, thereby shaping osteoclast priming, osteoblast suppression, and matrix turnover. Building on these mechanistic insights, we outline a translational framework that aligns standardized bone turnover markers of formation and resorption with composite panels of oxidative and nitrosative stress. This framework also integrates modern imaging to capture structural injury and metabolically active marrow disease. We further propose a therapeutic roadmap layered on antiresorptive foundations that targets selective inhibition of nicotinamide adenine dinucleotide phosphate oxidase 4 and calibrated modulation of nuclear factor erythroid 2\u2013related factor 2, disrupts damage-associated molecular pattern and cytokine circuits, and applies lineage- and timing-specific tuning of autophagy together with restoration of ferroportin-1 or iron chelation. This integrated strategy is designed to recouple bone remodeling and improve clinically meaningful skeletal outcomes in multiple myeloma.<\/jats:p>","DOI":"10.3390\/biom16050710","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T16:46:18Z","timestamp":1779381978000},"page":"710","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Microenvironmental Drivers of Bone Disease in Multiple Myeloma: Oxidative Stress, Sterile Inflammation, Autophagy\u2013Lysosomal Remodeling, and the Iron\u2013Lipid Peroxidation Axis"],"prefix":"10.3390","volume":"16","author":[{"given":"Maria Elisa","family":"Nasso","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Human Pathology in Adulthood and Childhood \u201cGaetano Barresi\u201d, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adele","family":"Bottaro","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Human Pathology in Adulthood and Childhood \u201cGaetano Barresi\u201d, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8804-2640","authenticated-orcid":false,"given":"Manlio","family":"Fazio","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Human Pathology in Adulthood and Childhood \u201cGaetano Barresi\u201d, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7947-158X","authenticated-orcid":false,"given":"Fabio","family":"Stagno","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Human Pathology in Adulthood and Childhood \u201cGaetano Barresi\u201d, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiano","family":"Gangemi","sequence":"additional","affiliation":[{"name":"Allergy and Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6156-8239","authenticated-orcid":false,"given":"Alessandro","family":"Allegra","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Human Pathology in Adulthood and Childhood \u201cGaetano Barresi\u201d, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1182\/blood-2018-11-852459","article-title":"Myeloma bone disease: From biology findings to treatment approaches","volume":"133","author":"Terpos","year":"2019","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41408-017-0037-4","article-title":"Pathogenesis of bone disease in multiple myeloma: From bench to bedside","volume":"8","author":"Terpos","year":"2018","journal-title":"Blood Cancer J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7665","DOI":"10.1158\/0008-5472.CAN-06-4666","article-title":"Production of Wnt inhibitors by myeloma cells: Potential effects on the bone microenvironment","volume":"67","author":"Giuliani","year":"2007","journal-title":"Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1182\/blood-2002-09-2684","article-title":"RANK ligand and osteoprotegerin in myeloma bone disease","volume":"101","author":"Sezer","year":"2003","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e27","DOI":"10.1038\/bcj.2011.22","article-title":"Myeloma cells suppress osteoblasts through sclerostin secretion","volume":"1","author":"Colucci","year":"2011","journal-title":"Blood Cancer J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00280-024-04736-7","article-title":"Sulforaphane inhibits multiple myeloma cell-induced osteoclast differentiation and macrophage proliferation by elevating ferroportin1","volume":"95","author":"Sun","year":"2024","journal-title":"Cancer Chemother. 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