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<\/figure>PC18 – Joanna\u00a0Izabela Lachowicz\u00a0<\/strong><\/p>\n\n\n\n Wroclaw Medical University, Poland joanna.lachowicz@umw.edu.pl<\/strong><\/p>\n<\/div><\/div>\n\n\n\n <\/p>\n","protected":false},"excerpt":{"rendered":" PC18 – Joanna\u00a0Izabela Lachowicz\u00a0 Wroclaw Medical University, PolandUniversity of Cagliari, Italy joanna.lachowicz@umw.edu.pl Thymosin \u03b24 as a Metal\u2011Responsive Regulator of Ferroptosis and Cellular Stress: Implications for Medicinal Chemistry Joanna Izabela Lachowicz1,2 1 Department of Environmental Health, Occupational Medicine […]<\/p>\n","protected":false},"author":10371,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1],"tags":[],"class_list":["post-2011","post","type-post","status-publish","format-standard","hentry","category-senza-categoria"],"_links":{"self":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/2011","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/users\/10371"}],"replies":[{"embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/comments?post=2011"}],"version-history":[{"count":5,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/2011\/revisions"}],"predecessor-version":[{"id":2341,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/2011\/revisions\/2341"}],"wp:attachment":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/media?parent=2011"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/categories?post=2011"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/tags?post=2011"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
University of Cagliari, Italy<\/p>\n\n\n\nThymosin \u03b24 as a Metal\u2011Responsive Regulator of Ferroptosis and Cellular Stress: Implications for Medicinal Chemistry<\/strong><\/td><\/tr> Joanna Izabela Lachowicz<\/em>1<\/em><\/sup>,2<\/sup><\/em>
1<\/sup><\/em> Department of Environmental Health, Occupational Medicine and Epidemiology, Wroclaw Medical University, Mikulicza-Radeckiego 7, 50-368 Wroclaw, PL, Poland
2<\/sup><\/em> Department of Medical Science and Public Health, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, CA, Italy<\/td><\/tr>Abstract<\/strong>
Thymosin \u03b24 (T\u03b24) is a highly conserved, intrinsically disordered peptide with established roles in actin dynamics, tissue regeneration, angiogenesis, inflammation, and cancer progression [1]. However, its pleiotropic biological activity cannot be fully explained by G\u2011actin sequestration alone. Here, we propose an integrated mechanistic model in which T\u03b24 functions as a metal\u2011responsive regulator of cellular stress and ferroptosis, with direct relevance for medicinal chemistry.
Using NMR spectroscopy, molecular modeling, and cellular assays, we demonstrate that T\u03b24 coordinates essential metal ions\u2014including Fe\u00b2\u207a\/Fe\u00b3\u207a, Zn\u00b2\u207a, and Ca\u00b2\u207a\u2014via multiple low\u2011affinity, spatially distributed binding sites [1\u20133]. Structural analyses reveal that metal coordination does not induce major secondary\u2011structure rearrangements, consistent with the intrinsically disordered nature of the peptide [2]. Functionally, T\u03b24 acts as an endogenous iron chelator, forming dynamic complexes that modulate iron availability and redox balance under stress conditions [1].
In macrophage models, extracellular T\u03b24 suppresses erastin\u2011 and glutamate\u2011induced ferroptosis, reverses mitochondrial ultrastructural damage, and restores cellular organization [1]. At the molecular level, T\u03b24 counteracts ferroptotic cell death by upregulating oxidative\u2011stress response genes (HO\u20111, HSP70, BAX, TXNRD1) that are otherwise suppressed during lipid peroxidation\u2011driven toxicity [1]. Its anti\u2011ferroptotic efficacy parallels that of reference ferroptosis inhibitors, suggesting a shared metal\u2011dependent mechanism rather than a purely antioxidant effect.
We further show that nutrient starvation profoundly alters T\u03b24 trafficking, promoting the cellular uptake of extracellular T\u03b24 and its Ca\u00b2\u207a complexes [3]. Under these conditions, Ca\u00b2\u207a\/T\u03b24 complexes are internalized into the cytoplasm, increasing intracellular calcium availability and potentially activating migration\u2011 and survival\u2011associated signaling pathways relevant to early metastatic events [3]. Complementary zinc\u2011coordination studies support an additional role for T\u03b24 in intracellular metal buffering and redox modulation during inflammation and cellular stress [2].
Collectively, these findings establish T\u03b24 as a multifunctional, redox\u2011active metallopeptide that integrates metal coordination, ferroptosis regulation, and stress adaptation. From a medicinal chemistry perspective, T\u03b24 provides a biological blueprint for designing non\u2011toxic, peptide\u2011based metal modulators, opening new strategies for targeting ferroptosis and metal\u2011driven pathologies in cancer, neurodegeneration, and tissue injury.<\/td><\/tr>References <\/strong>
[1] Lachowicz, J.I.; Pichiri, G.; Piludu, M.; Fais, S.; Orr\u00f9, G.; Congiu, T.; Piras, M.; Faa, G.; Fanni, D.; Dalla Torre, G.; et\u202fal. Thymosin \u03b24 Is an Endogenous Iron Chelator and Molecular Switcher of Ferroptosis. Int. J. Mol. Sci. 2022, 23, 551.
[2] Lachowicz, J.I.; Jaremko, M.; Jaremko, \u0141.; Pichiri, G.; Coni, P.; Piludu, M. Metal Coordination of Thymosin \u03b24: Chemistry and Possible Implications. Coord. Chem. Rev. 2019, 396, 117\u2013123.
[3] Piludu, M.; Pichiri, G.; Coni, P.; Piras, M.; Congiu, T.; Faa, G.; Lachowicz, J.I. Cell Starvation Increases Uptake of Extracellular Thymosin \u03b24 and Its Complexes with Calcium. Int. Immunopharmacol. 2023, 116, 109743.<\/td><\/tr><\/tbody><\/table><\/div><\/figure>\n\n\n\n