{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T19:47:41Z","timestamp":1777319261908,"version":"3.51.4"},"reference-count":44,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Benzodioxane\u2010derived hydrazones (BDHs) have emerged as promising antioxidant agents due to their redox\u2010modulatory properties, structural versatility, and ability to activate cellular defense pathways. This study evaluated the protective potential of two BDH derivatives\u2014MBDH (methoxy\u2010substituted) and TBDH (thiophene\u2010substituted)\u2014against Cd\u2010induced toxicity, a major environmental health concern associated with multi\u2010organ dysfunction via oxidative stress and mitochondrial impairment. Using LC\u2010MS\/MS\u2010based metabolomic profiling together with biochemical assays in a mouse model, we compared the efficacy of BDHs with that of ascorbic acid. Cd exposure resulted in significant metabolic disruption, including reduced levels of amino acids (serine, methionine), elevated lipid peroxidation products (ceramides, phospholipid fragments), and mitochondrial dysfunction. Ascorbic acid (AA) provided partial metabolic and histological protection. MBDH exhibited moderate effects by reducing lipid peroxidation markers and partially restoring some amino acid levels, with a hydroxylated metabolite detected at m\/z 328. TBDH, however, demonstrated superior protection, with near\u2010complete normalization of metabolic profiles, formation of a stable metabolite (m\/z 304), and marked attenuation in lipid peroxidation. Additionally, TBDH activated the Nrf2 signaling pathway, increased intracellular glutathione levels, and significantly improved histopathology in the liver, brain, and pancreas. It also reduced the levels of systemic inflammatory markers such as CRP, ESR, and procalcitonin. The enhanced performance of TBDH is attributed to its thiophene moiety, which facilitates improved electron delocalization and redox potential. This study highlights TBDH as a potent Nrf2 activator and antioxidant agent capable of mitigating Cd\u2010induced metabolic and oxidative damage, providing a strong basis for the development of BDH\u2010based therapeutics targeting heavy metal toxicity and related oxidative stress disorders.<\/jats:p>","DOI":"10.1002\/jbt.70869","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T19:07:36Z","timestamp":1777316856000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Metabolomic and Biochemical Profiling of Benzodioxane\u2010Derived Hydrazones Targeting Nrf2 to Mitigate Cadmium\u2010Induced Metabolic Dysregulation"],"prefix":"10.1002","volume":"40","author":[{"given":"Aisha","family":"Rafique","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry Government College University Faisalabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9446-5233","authenticated-orcid":false,"given":"Muhammad Sajid Hamid","family":"Akash","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry Government College University Faisalabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shagufta","family":"Kamal","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Government College University Faisalabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kanwal","family":"Rehman","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The Women University Multan Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Usama","family":"Munir","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry Government College University Faisalabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sehar","family":"Madni","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry Government College University Faisalabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.molstruc.2025.141442","article-title":"Synthesis, Characterization and Biological Evaluation of indole\u20103\u2010acetic Acid\u2010Based Hydrazone Derivatives","volume":"1329","author":"Munir M. 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