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This drug inhibits cyclooxygenase-1 and cyclooxygenase-2 enzymes, which are responsible for the generation of prostaglandin synthesis. To improve current diclofenac-based therapies, we require new molecular systematic therapeutic approaches to reduce complex multifactorial effects. However, the critical challenge that appears with diclofenac and other drugs of the same class is their side effects, such as signs of stomach injuries, kidney problems, cardiovascular issues, hepatic issues, and diarrhea. In this article, we discuss why defining diclofenac-based mechanisms, pharmacological features, and its medicinal properties are needed to direct future drug development against neurodegeneration and imperfect ageing and to improve cancer therapy. In addition, we describe various advance molecular mechanisms and fundamental aspects linked with diclofenac which can strengthen and enable the better designing of new derivatives of diclofenac to overcome critical challenges and improve their applications.<\/jats:p>","DOI":"10.3390\/cancers14184385","type":"journal-article","created":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T04:54:41Z","timestamp":1662699281000},"page":"4385","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Development and Challenges of Diclofenac-Based Novel Therapeutics: Targeting Cancer and Complex Diseases"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8782-1298","authenticated-orcid":false,"given":"Ayeman","family":"Amanullah","sequence":"first","affiliation":[{"name":"Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur 342037, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3216-1277","authenticated-orcid":false,"given":"Arun","family":"Upadhyay","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur 342037, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohan","family":"Dhiman","sequence":"additional","affiliation":[{"name":"Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarika","family":"Singh","sequence":"additional","affiliation":[{"name":"Division of Toxicology and Experimental Medicine, Department of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore 453552, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh Kumar","family":"Ahirwar","sequence":"additional","affiliation":[{"name":"Tumor Microenvironment Unit, Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342037, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0912-5796","authenticated-orcid":false,"given":"Ravi Kumar","family":"Gutti","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Hyderabad, Hyderabad 500046, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9401-4400","authenticated-orcid":false,"given":"Amit","family":"Mishra","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur 342037, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.molmed.2008.08.005","article-title":"Arachidonic-acid-derived eicosanoids: Roles in biology and immunopathology","volume":"14","author":"Harizi","year":"2008","journal-title":"Trends Mol. 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