{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T16:29:12Z","timestamp":1782491352193,"version":"3.54.5"},"reference-count":120,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T00:00:00Z","timestamp":1744156800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AIRC","award":["IG 2017 ID 19786"],"award-info":[{"award-number":["IG 2017 ID 19786"]}]},{"name":"AIRC","award":["IG 2024 ID 30707"],"award-info":[{"award-number":["IG 2024 ID 30707"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The Lon protease homolog 1 (LONP1) is an ATP-dependent mitochondrial protease essential for maintaining proteostasis, bioenergetics, and cellular homeostasis. LONP1 plays a pivotal role in protein quality control, mitochondrial DNA maintenance, and oxidative phosphorylation system (OXPHOS) regulation, particularly under stress conditions. Dysregulation of LONP1 has been implicated in various pathologies, including cancer, metabolic disorders, and reproductive diseases, positioning it as a promising pharmacological target. This review examines compounds that modulate LONP1 activity, categorizing them into inhibitors and activators. Inhibitors such as CDDO and its derivatives selectively target LONP1, impairing mitochondrial proteolysis, inducing protein aggregation, and promoting apoptosis, particularly in cancer cells. Compounds like Obtusilactone A and proteasome inhibitors (e.g., MG262) demonstrate potent cytotoxicity, further expanding the therapeutic landscape. Conversely, LONP1 activators, including Artemisinin derivatives and 84-B10, restore mitochondrial function and protect against conditions such as polycystic ovary syndrome (PCOS) and acute kidney injury (AKI). Future research should focus on improving the specificity, bioavailability, and pharmacokinetics of these modulators. Advances in structural biology and drug discovery will enable the development of novel LONP1-targeted therapies, addressing diseases driven by mitochondrial dysfunction and proteostasis imbalance.<\/jats:p>","DOI":"10.3390\/biom15040553","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T12:05:56Z","timestamp":1744200356000},"page":"553","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Modulation of Lonp1 Activity by Small Compounds"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6285-4314","authenticated-orcid":false,"given":"Giada","family":"Zanini","sequence":"first","affiliation":[{"name":"Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Micheloni","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Sinigaglia","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Selleri","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"},{"name":"National Institute for Cardiovascular Research\u2014INRC, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1487-9530","authenticated-orcid":false,"given":"Anna Vittoria","family":"Mattioli","sequence":"additional","affiliation":[{"name":"National Institute for Cardiovascular Research\u2014INRC, 40126 Bologna, Italy"},{"name":"Department of Quality-of-Life Sciences, University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3079-8001","authenticated-orcid":false,"given":"Milena","family":"Nasi","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1816-548X","authenticated-orcid":false,"given":"Ciro Leonardo","family":"Pierri","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Pharmaceutical Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9118-1262","authenticated-orcid":false,"given":"Marcello","family":"Pinti","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"},{"name":"National Institute for Cardiovascular Research\u2014INRC, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e681","DOI":"10.1038\/cddis.2013.204","article-title":"Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species","volume":"4","author":"Cheng","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/j.celrep.2014.06.018","article-title":"ATP-dependent Lon protease controls tumor bioenergetics by reprogramming mitochondrial activity","volume":"8","author":"Quiros","year":"2014","journal-title":"Cell Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"77457","DOI":"10.18632\/oncotarget.12681","article-title":"Mitochondrial Lon is over-expressed in high-grade gliomas, and mediates hypoxic adaptation: Potential role of Lon as a therapeutic target in glioma","volume":"7","author":"Di","year":"2016","journal-title":"Oncotarget"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Gibellini, L., Losi, L., De Biasi, S., Nasi, M., Lo Tartaro, D., Pecorini, S., Patergnani, S., Pinton, P., De Gaetano, A., and Carnevale, G. 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