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Unfortunately, current drugs have limited efficacy, side effects and can lead to chemoresistance. Therefore, searching for a nontoxic, efficacious anti\u2010mCRC agent is crucial and of utmost interest. The present study demonstrates the identification of a productive and nontoxic anti\u2010mCRC agent through a five\u2010targets (\u03b2\u2010catenin, GSK\u20103\u03b2, PI3K\u2010\u03b1, AKT1, and p50)\u2010based and three\u2010tier (binding affinity, pharmacokinetics, and pharmacophore) screening strategy involving a series of 30 phytocompounds having a background of anti\u2010inflammatory\/anti\u2010mCRC efficacy alongside 5\u2010fluorouracil (FU), a reference drug. Luteolin (a phyto\u2010flavonoid) was eventually rendered as the most potent and safe phytocompound. This inference was verified through three rounds of validation. Firstly, luteolin was found to be effective against the different mCRC cell lines (HCT\u201015, HCT\u2010116, DLD\u20101, and HT\u201029) without hampering the viability of non\u2010tumorigenic ones (RWPE\u20101). Secondly, luteolin was found to curtail the clonogenicity of CRC cells, and finally, it also disrupted the formation of colospheroids, a characteristic of metastasis. While studying the mechanistic insights, luteolin was found to inhibit \u03b2\u2010catenin activity (a key regulator of mCRC) through direct physical interactions, promoting its degradation by activating GSK3\u2010\u03b2 and ceasing its activation by inactivating AKT1 and PI3K\u2010\u03b1. Luteolin also inhibited p50 activity, which could be useful in mitigating mCRC\u2010associated proinflammatory milieu. In conclusion, our study provides evidence on the efficacy of luteolin against the critical key regulators of immunopathogenesis of mCRC and recommends further studies in animal models to determine the effectiveness efficacy of this natural compound for treating mCRC in the future.<\/jats:p>","DOI":"10.1002\/jcb.30654","type":"journal-article","created":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T07:26:08Z","timestamp":1726817168000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Revisiting Luteolin Against the Mediators of Human Metastatic Colorectal Carcinoma: A Biomolecular Approach"],"prefix":"10.1002","volume":"126","author":[{"given":"Ankita","family":"Chakraborty","sequence":"first","affiliation":[{"name":"Integrative Biochemistry and Immunology Laboratory, Department of Animal Science Kazi Nazrul University Asansol West Bengal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Advaitha","family":"Midde","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pritha","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Integrative Biochemistry and Immunology Laboratory, Department of Animal Science Kazi Nazrul University Asansol West Bengal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sourin","family":"Adhikary","sequence":"additional","affiliation":[{"name":"Integrative Biochemistry and Immunology Laboratory, Department of Animal Science Kazi Nazrul University Asansol West Bengal India"},{"name":"Food Toxicology Laboratory, Food, Drug, and Chemical Toxicology Group CSIR\u2010Indian Institute of Toxicology Research Lucknow Uttar Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simran","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navpreet","family":"Arri","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabarun","family":"Chandra Das","sequence":"additional","affiliation":[{"name":"Integrative Biochemistry and Immunology Laboratory, Department of Animal Science Kazi Nazrul University Asansol West Bengal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parth Sarthi","family":"Sen Gupta","sequence":"additional","affiliation":[{"name":"School of Biosciences and Bioengineering D. 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