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Fluorescence microscopy maps organelle structures with subcellular resolution but provides limited chemical information. Infrared (IR) imaging offers a label\u2010free alternative for probing intrinsic molecular vibrations that report on lipids, carbohydrates, and nucleic acids. Here, we combine submicron optical photothermal IR imaging with machine learning to classify subcellular structures in fixed U\u20102 OS cells in a cell state dependent manner. Using fluorescent\u2010labeled organelles as ground truth, we trained and evaluated random forest (RF) classifiers and U\u2010Net convolutional neural networks to identify organelles from IR spectra in healthy cells. The classifiers accurately identified multiple organelles, including the endoplasmic reticulum, Golgi apparatus, mitochondria, nucleus, nucleolus, and stress granules. Classifiers trained in U\u20102 OS cells transferred without retraining to HEK 293 cells, consistent with conserved organelle biochemical composition across cell types. Conversely, the classifiers failed under cellular stress which indicates sensitivity to stress\u2010induced changes in organelle state. Together, these results establish a scalable, label\u2010free strategy for high\u2010resolution mapping of organelle biochemical composition and provide a foundation for subcellular biomarker discovery and disease\u2010state diagnostics.<\/jats:p>","DOI":"10.1002\/smtd.71080","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:53:53Z","timestamp":1791266033000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optical Photothermal Infrared Signatures Distinguish Organelle Identity and Health in Single Cells"],"prefix":"10.1002","author":[{"given":"Michael J.","family":"Burke","sequence":"first","affiliation":[{"name":"Department of Chemistry Yale University  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3262-1237","authenticated-orcid":false,"given":"Victor 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