{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T10:50:51Z","timestamp":1767955851929,"version":"3.49.0"},"reference-count":42,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:00:00Z","timestamp":1767916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Indonesian Endowment Fund for Education (LPDP) of the Ministry of Higher Education, Science, and Technology","award":["4303\/B3\/DT.03.08\/2025"],"award-info":[{"award-number":["4303\/B3\/DT.03.08\/2025"]}]},{"name":"Indonesian Endowment Fund for Education (LPDP) of the Ministry of Higher Education, Science, and Technology","award":["3927\/UN6.RKT\/HK.07.00\/2025"],"award-info":[{"award-number":["3927\/UN6.RKT\/HK.07.00\/2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>The liver stage of Plasmodium infection represents a critical bottleneck in malaria pathogenesis and a unique interface between parasite development and hepatocyte-intrinsic immunity. Recent evidence suggests that hepatocytes do not eliminate liver-stage parasites through canonical xenophagy, as previously assumed, but instead employ a noncanonical autophagy response known as the conjugation of ATG8 to single membranes (CASM). CASM drives rapid lipidation of LC3 onto the parasitophorous vacuole membrane (PVM) via a V-ATPase-ATG16L1-dependent mechanism, thereby activating the Plasmodium-associated autophagy-related (PAAR) response. This process represents a major hepatocyte-intrinsic mechanism that limits early liver-stage parasite development. Plasmodium liver-stage parasites have evolved specialized strategies to counteract this host defense. The PVM proteins UIS3 and UIS4 enable parasite evasion by sequestering LC3 and remodeling perivacuolar actin, thereby preventing endolysosomal fusion and inhibiting PAAR execution. In parallel, parasites selectively exploit host autophagy components\u2014particularly GABARAP paralogs\u2014to activate TFEB, promoting lysosomal biogenesis and improving access to host-derived nutrients. These interactions highlight autophagy as both a protective and parasite-supportive pathway, depending on the molecular context. Understanding how CASM, PAAR, and parasite evasion mechanisms intersect is crucial for designing pathway-selective interventions that amplify hepatocyte-intrinsic clearance while avoiding the inadvertent enhancement of parasite-supportive autophagy programs. Selective modulation of noncanonical autophagy offers a promising avenue for host-directed therapies that restrict liver-stage development while limiting the emergence of antimalarial resistance. This review synthesizes recent advances in the mechanistic interplay between Plasmodium liver stages and hepatocyte autophagy, identifies major knowledge gaps, and outlines future directions for translating these discoveries into therapeutic innovation.<\/jats:p>","DOI":"10.3390\/pathogens15010070","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T09:25:02Z","timestamp":1767950702000},"page":"70","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatocyte Autophagy in Malaria: Current Concepts, Emerging Mechanisms, and Future Therapeutic Directions"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8809-0810","authenticated-orcid":false,"given":"Afiat","family":"Berbudi","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Parasitology Division, Faculty of Medicine, Universitas Padjadjaran, Bandung 40161, Indonesia"},{"name":"Research Center for Care and Control of Infectious Diseases (RC3ID), Universitas Padjadjaran, Bandung 40161, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6225-1388","authenticated-orcid":false,"given":"Shafia","family":"Khairani","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Cell Biology Division, Faculty of Medicine, Universitas Padjadjaran, Bandung 40161, Indonesia"},{"name":"Veterinary Medicine Program, Faculty of Medicine, Universitas Padjadjaran, Sumedang 45363, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7587-9608","authenticated-orcid":false,"given":"Endang Yuni","family":"Setyowati","sequence":"additional","affiliation":[{"name":"Veterinary Medicine Program, Faculty of Medicine, Universitas Padjadjaran, Sumedang 45363, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0893-2908","authenticated-orcid":false,"given":"Alexander","family":"Kwarteng","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology, PMB University Post Office, Kumasi, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"World Health Organization (2024). World Malaria Report 2024: Addressing Inequity in the Global Malaria Response, World Health Organization. Available online: https:\/\/www.who.int\/teams\/global-malaria-programme\/reports\/world-malaria-report-2024.","DOI":"10.30875\/9789287076717"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhu, C., Jiao, S., and Xu, W. (2024). CD8+ Trms against malaria liver-stage: Prospects and challenges. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1344941"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"104224","DOI":"10.1016\/j.isci.2022.104224","article-title":"A Plasmodium falciparum ATP-binding cassette transporter is essential for liver stage entry into schizogony","volume":"25","author":"Goswami","year":"2022","journal-title":"iScience"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Roques, M., Bindschedler, A., Beyeler, R., and Heussler, V.T. (2023). Same, same but different: Exploring Plasmodium cell division during liver stage development. PLoS Pathog., 19.","DOI":"10.1371\/journal.ppat.1011210"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7690","DOI":"10.1038\/ncomms8690","article-title":"Plasmodium falciparum full life cycle and Plasmodium ovale liver stages in humanized mice","volume":"6","author":"Soulard","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.pt.2019.11.006","article-title":"Hardly Vacuous: The Parasitophorous Vacuolar Membrane of Malaria Parasites","volume":"36","author":"Goldberg","year":"2019","journal-title":"Trends Parasitol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Posfai, D., Sylvester, K., Reddy, A., Ganley, J.G., Wirth, J., Cullen, Q.E., Dave, T., Kato, N., Dave, S.S., and Derbyshire, E.R. (2018). Plasmodium Parasite Exploits Host Aquaporin-3 During Liver Stage Malaria Infection. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007057"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e00139-17","DOI":"10.1128\/mBio.00139-17","article-title":"Manipulation of the Host Cell Membrane during Plasmodium Liver Stage Egress","volume":"8","author":"Burda","year":"2017","journal-title":"mBio"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1093\/femsre\/fuy007","article-title":"Host cell cytosolic immune response during Plasmodium liver stage development","volume":"42","author":"Niklaus","year":"2018","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7967","DOI":"10.1038\/s41598-019-44449-z","article-title":"Deciphering host lysosome-mediated elimination of Plasmodium berghei liver stage parasites","volume":"9","author":"Niklaus","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"E3519","DOI":"10.1073\/pnas.1525606113","article-title":"LAP-like Process as an Immune Mechanism Downstream of IFN-\u03b3 in Control of the Human Malaria Plasmodium vivax liver Stage","volume":"113","author":"Boonhok","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41564-017-0054-x","article-title":"Plasmodium UIS3 sequesters host LC3 to avoid elimination by autophagy in hepatocytes","volume":"3","author":"Real","year":"2018","journal-title":"Nat. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/s42003-020-01422-1","article-title":"Disrupting Plasmodium UIS3\u2013host LC3 interaction with a small molecule causes parasite elimination from host cells","volume":"3","author":"Setua","year":"2020","journal-title":"Commun. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e12754","DOI":"10.1111\/cmi.12754","article-title":"LC3-association with the parasitophorous vacuole membrane of Plasmodium berghei liver stages follows a noncanonical autophagy pathway","volume":"19","author":"Wacker","year":"2017","journal-title":"Cell Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1111\/mmi.15259","article-title":"LC3B labeling of the parasitophorous vacuole membrane of Plasmodium berghei liver stage parasites depends on the V-ATPase and ATG16L1","volume":"121","author":"Bindschedler","year":"2024","journal-title":"Mol. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"112052","DOI":"10.1016\/j.isci.2025.112052","article-title":"Elimination of intra-hepatocytic malaria parasites is driven by non-canonical autophagy but not nitric oxide production","volume":"28","author":"Schepis","year":"2025","journal-title":"iScience"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e0273524","DOI":"10.1128\/mbio.02735-24","article-title":"Autophagy protein Atg7 is essential for maintaining malaria parasite cellular homeostasis and organelle biogenesis","volume":"16","author":"Mishra","year":"2025","journal-title":"mBio"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Gomes-Santos, C.S.S., Itoe, M.A., Afonso, C., Henriques, R., Gardner, R., Sep\u00falveda, N., Sim\u00f5es, P.D., Raquel, H., Almeida, A.P., and Moita, L.F. (2012). Highly dynamic host actin reorganization around developing Plasmodium inside hepatocytes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0029408"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1091\/mbc.e16-07-0531","article-title":"Sequestration of cholesterol within the host late endocytic pathway restricts liver-stage Plasmodium development","volume":"28","author":"Petersen","year":"2017","journal-title":"Mol. Biol. Cell."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1038\/s42003-024-07242-x","article-title":"Plasmodium berghei liver stage parasites exploit host GABARAP proteins for TFEB activation","volume":"7","author":"Bindschedler","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Leleu, I., Alloo, J., Cazenave, P.-A., Roland, J., and Pied, S. (2022). Autophagy Pathways in the Genesis of Plasmodium-Derived Microvesicles: A Double-Edged Sword?. Life, 12.","DOI":"10.3390\/life12030415"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.15252\/embj.201695500","article-title":"A postprandial FGF19-SHP-LSD1 regulatory axis mediates epigenetic repression of hepatic autophagy","volume":"36","author":"Byun","year":"2017","journal-title":"EMBO J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3283","DOI":"10.4049\/jimmunol.1601920","article-title":"PPAR-\u03b1 Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism","volume":"198","author":"Kim","year":"2017","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"111927","DOI":"10.1016\/j.celrep.2022.111927","article-title":"Malaria parasites harness Rho GTPase signaling and host cell membrane ruffling for productive invasion of hepatocytes","volume":"42","author":"Schepis","year":"2023","journal-title":"Cell Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1126\/science.1129720","article-title":"Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids","volume":"313","author":"Sturm","year":"2006","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.chom.2015.10.006","article-title":"Malaria Sporozoites Traverse Host Cells within Transient Vacuoles","volume":"18","author":"Marinach","year":"2015","journal-title":"Cell Host Microbe"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Schmuckli-Maurer, J., Reber, V., Wacker, R., Bindschedler, A., Zakher, A., and Heussler, V.T. (2017). Inverted recruitment of autophagy proteins to the Plasmodium berghei parasitophorous vacuole membrane. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183797"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"eabo1274","DOI":"10.1126\/sciadv.abo1274","article-title":"Many roads lead to CASM: Diverse stimuli of noncanonical autophagy share a unifying molecular mechanism","volume":"8","author":"Durgan","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Hooper, K.M., Jacquin, E., Li, T., Goodwin, J.M., Brumell, J.H., Durgan, J., and Florey, O. (2021). V-ATPase is a universal regulator of LC3 associated phagocytosis and non-canonical autophagy. bioRxiv.","DOI":"10.1101\/2021.05.20.444917"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"jcs259725","DOI":"10.1242\/jcs.259725","article-title":"Post-translational modifications of ATG8 proteins\u2014An emerging mechanism of autophagy control","volume":"136","author":"Zaretski","year":"2023","journal-title":"J. Cell Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"26824","DOI":"10.1038\/srep26824","article-title":"Protective efficacy and safety of liver stage attenuated malaria parasites","volume":"6","author":"Kumar","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_32","first-page":"1116","article-title":"Effect of autophagy on liver regeneration","volume":"37","author":"Wang","year":"2015","journal-title":"Hereditas"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1080\/15548627.2015.1067361","article-title":"Long-term live imaging reveals cytosolic immune responses of host hepatocytes against Plasmodium infection and parasite escape mechanisms","volume":"11","author":"Prado","year":"2015","journal-title":"Autophagy"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"433","DOI":"10.2174\/1567205011310040008","article-title":"Autophagy Enhancer Carbamazepine Alleviates Memory Deficits and Cerebral Amyloid-\u03b2 Pathology in a Mouse Model of Alzheimer\u2019s Disease","volume":"10","author":"Li","year":"2013","journal-title":"Curr. Alzheimer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.pt.2024.04.004","article-title":"Hepatocytes and the art of killing Plasmodium softly","volume":"40","author":"Kurup","year":"2024","journal-title":"Trends Parasitol."},{"key":"ref_36","first-page":"E1138","article-title":"Plasmodium berghei EXP-1 interacts with host Apolipoprotein H during Plasmodium liver-stage development","volume":"114","author":"Nyboer","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1158\/2159-8290.CD-17-0741","article-title":"A unified approach to targeting the lysosome\u2019s degradative and growth signaling roles","volume":"7","author":"Rebecca","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2191918","DOI":"10.1080\/27694127.2023.2191918","article-title":"Survival of intracellular pathogens in response to mTORC1- or TRPML1-TFEB-induced xenophagy","volume":"2","author":"Capurro","year":"2023","journal-title":"Autophagy Rep."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Portugal, S., Rodriguez, A., Prud\u00eancio, M., and Maria, M. (2022). Mota: Bringing Plasmodium Liver Infection to the Centre Stage of Malaria Research. Front. Cell Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.851484"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4631","DOI":"10.1038\/s41467-023-40298-7","article-title":"Development of Plasmodium falciparum liver-stages in hepatocytes derived from human fetal liver organoid cultures","volume":"14","author":"Yang","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"45424","DOI":"10.1038\/srep45424","article-title":"Towards a Humanized Mouse Model of Liver Stage Malaria Using Ectopic Artificial Livers","volume":"7","author":"Ng","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e0517622","DOI":"10.1128\/spectrum.05176-22","article-title":"Liver humanized NSG-PiZ mice support the study of chronic hepatitis B virus infection and antiviral therapies","volume":"11","author":"Stone","year":"2023","journal-title":"Microbiol. Spectr."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/1\/70\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T09:32:10Z","timestamp":1767951130000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/1\/70"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,9]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["pathogens15010070"],"URL":"https:\/\/doi.org\/10.3390\/pathogens15010070","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,9]]}}}