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The apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is an essential enzyme of the base excision repair pathway of non‐distorting DNA lesions. In response to genotoxic treatments, APE1 is highly secreted (sAPE1) in association with small‐extracellular vesicles (EVs). Interestingly, its presence in the serum of patients with hepatocellular or non‐small‐cell‐lung cancers may represent a prognostic biomarker. The mechanism driving APE1 to associate with EVs is unknown, but is of paramount importance in better understanding the biological roles of sAPE1. Because APE1 lacks an endoplasmic reticulum‐targeting signal peptide, it can be secreted through an unconventional protein secretion endoplasmic reticulum–Golgi‐independent pathway, which includes an endosome‐based secretion of intraluminal vesicles, mediated by multivesicular bodies (MVBs). Using HeLa and A549 cell lines, we investigated the role of endosomal sorting complex required for transport protein pathways (either‐dependent or ‐independent) in the constitutive or trichostatin A‐induced secretion of sAPE1, by means of manumycin A and GW 4869 treatments. Through an in‐depth biochemical analysis of late‐endosomes (LEs) and early‐endosomes (EEs), we observed that the distribution of APE1 on density gradient corresponded to that of LE–CD63, LE–Rab7, EE–EEA1 and EE–Rab 5. Interestingly, the secretion of sAPE1, induced by cisplatin genotoxic stress, involved an autophagy‐based unconventional secretion requiring MVBs. The present study enlightens the central role played by MVBs in the secretion of sAPE1 under various stimuli, and offers new perspectives in understanding the biological relevance of sAPE1 in cancer cells. [ABSTRACT FROM AUTHOR]