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Genetic manipulation of the lipid metabolic network or supplementation of a high\u2010fat diet\/oleic acid (OA) are the traditional routes for voluntarily triggering LD formation in cells and animals to study the role of LDs in disease biology. We developed a new screening platform for identifying small molecule\u2010based LD inducers, which identified linoleic acid (LOA, diunsaturated fatty acid) as a better tool than OA (monounsaturated fatty acid) in promoting LD formation in cells. Subsequent screening and validation discovered a novel heterocyclic compound and respective iron complex for promoting a rapid organization of endogenous lipids into droplets by mimicking desaturase function and modulating oxidative lipid metabolism. Notably, our mass spectral lipidomics analysis presented the overproduction of phosphatidylcholines and small triglycerides (TG), a hallmark of LDs. We uncovered that the abrupt levels of LD formation induced by our molecules promoted a unique cell death mechanism, lysophagy in cancer cells, to prevent their proliferation, movement, and colonization. Collectively, our work introduces new small molecules as powerful tools for reliably promoting LD accumulation in cells, a promising tool for studying the role in health and disease.<\/jats:p>","DOI":"10.1002\/anie.202504595","type":"journal-article","created":{"date-parts":[[2025,7,26]],"date-time":"2025-07-26T13:20:33Z","timestamp":1753536033000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Small Molecule Promoters of Endogenous Lipid Droplet Accumulation Drive Lysophagy"],"prefix":"10.1002","volume":"64","author":[{"given":"Sai Kumari","family":"Vechalapu","sequence":"first","affiliation":[{"name":"Department of Chemistry Indian Institute of Technology Kanpur  Kalyanpur Uttar Pradesh 208016 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santhosh","family":"Duraisamy","sequence":"additional","affiliation":[{"name":"Department of Chemistry Indian Institute of Technology Kanpur  Kalyanpur Uttar Pradesh 208016 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sathyapriya","family":"Senthil","sequence":"additional","affiliation":[{"name":"Department of Chemistry Indian Institute of Technology Kanpur  Kalyanpur Uttar Pradesh 208016 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakesh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Chemistry Indian Institute of Technology Kanpur  Kalyanpur Uttar Pradesh 208016 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepa","family":"Ajnar","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Bioengineering Indian Institute of Technology Kanpur  Kalyanpur Uttar Pradesh 208016 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apparao","family":"Draksharapu","sequence":"additional","affiliation":[{"name":"Department of Chemistry Indian Institute of Technology Kanpur  Kalyanpur Uttar Pradesh 208016 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Bioengineering Indian Institute of Technology Kanpur  Kalyanpur Uttar Pradesh 208016 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1369-3611","authenticated-orcid":false,"given":"Dharmaraja","family":"Allimuthu","sequence":"additional","affiliation":[{"name":"Department of Chemistry Indian Institute of Technology Kanpur  Kalyanpur Uttar Pradesh 208016 India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,26]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-018-0085-z"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3699"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1006\/scdb.1998.0275"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.02941"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.138"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(01)00257-3"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2022.01.003"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207712200"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2017.11.020"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-023-00845-0"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2013.06.032"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2017.06.003"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8176"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature22369"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36432-0"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.03.003"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2019.146484"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3CC04829B"},{"key":"e_1_2_8_19_1","first-page":"3104","volume":"127","author":"Rohwedder A.","year":"2014","journal-title":"J. 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