{"doi":"10.4014/jmb.2509.09002","title":"Evaluating the Antifungal Potential of Autophagy-Related Protein 4 (ATG4) Inhibitors against Human Fungal Pathogens","abstract":"IntroductionInvasive fungal infections are one of the most challenging diseases to manage in human health today [1][2][3].The three most common systemic fungal infections in humans are caused by species of the genera, Aspergillus, Cryptococcus, and Candida [4].Cryptococcus neoformans, ranked among the top fungal pathogens on the World Health Organization's first Fungal Priority Pathogens List, is a globally distributed opportunistic fungus primarily originated from the environment [5].It poses a significant threat to human health, causing life-threatening cryptococcosis, particularly in immunocompromised individuals [6].Despite its serious impact on human health, C. neoformans infections are often ignored, emphasizing the urgent need to unravel its molecular pathogenesis for the development of new therapeutic options.Aspergillus fumigatus is responsible for severe respiratory infections.Invasive pulmonary aspergillosis (IPA) accounts for an estimated 200,000 cases annually [7].IPA is an aggressive and often fatal disease that primarily affects individuals undergoing chemotherapy, organ transplantation, or suffering from advanced pulmonary diseases [8,9].Similarly, Candida auris has emerged as a multidrug-resistant yeast responsible for bloodstream infections with high mortality rates.In the United States, clinical cases of C. auris surged by 60% in 2020 and doubled in 2021, highlighting its increasing prevalence [10].The current available antifungal agents, consisting of polyenes, azoles, and echinocandins, are insufficient to manage the mortality caused by fungal infections due to significant off-target effects, the rapid emergence of resistance to antifungal therapeutics, and the emergence of intrinsically drug-resistant fungal pathogens [11].Therefore, in addition to the development of new formulations of commercially available antifungal drugs, there is an urgent need for the development of alternative classes of broad-spectrum antifungal drugs that are fastacting and safe.Autophagy, often referred to as the self-eating machinery, is a fundamental process that maintains intracellular homeostasis by recycling or degrading unnecessary or damaged components, particularly under unfavorable growth conditions [12].It plays a crucial role in various biological functions, including nutrient sensing, cellular differentiation, tissue homeostasis, aging, immunity, and programmed cell death [13].More than 30 autophagy-Emerging fungal pathogens pose a significant threat to global public health.Despite the availability of antifungal agents, their clinical efficacy is increasingly challenged by the rise of fungicideresistant strains.Therefore, identifying novel therapeutic targets and ensuring the safe application of antifungal agents are critical for advancing treatment strategies.Autophagy, a fundamental cellular process that maintains intracellular homeostasis by degrading and recycling dysfunctional proteins and organelles, is implicated in fungal pathogenicity.It indicates that inhibition of autophagy represents a promising approach for antifungal development.In this study, we evaluate the antifungal potential of autophagy inhibitors targeting the Autophagy-related protein 4 (ATG4)mediated cleavage of Autophagy-related protein 8 (ATG8).Our findings demonstrate that ebselen and its analogs effectively inhibit ATG4 activity in Cryptococcus neoformans, Aspergillus fumigatus, and Aspergillus niger, exhibiting fungicidal activity against Cryptococcus and Candida species.These results provide valuable insights into novel antifungal development strategies, highlighting the therapeutic potential of autophagy inhibitors against diverse pathogenic fungi.","journal":"Journal of Microbiology and Biotechnology","year":2025,"id":535821,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9663,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1179333,"name":"Jongchan Woo","orcid":"0000-0002-2994-6444","position":1,"is_corresponding":false},{"id":1420021,"name":"Hyunjin Cha","orcid":"0000-0002-5759-5581","position":2,"is_corresponding":false},{"id":322501,"name":"Seung‐Heon Lee","orcid":"0000-0002-0578-7653","position":3,"is_corresponding":false},{"id":1383410,"name":"Sagar Dahal","orcid":null,"position":4,"is_corresponding":false},{"id":322518,"name":"Yong‐Sun Bahn","orcid":"0000-0001-9573-5752","position":5,"is_corresponding":false},{"id":1179339,"name":"Eunsook Park","orcid":"0000-0003-2984-3039","position":6,"is_corresponding":false},{"id":1179338,"name":"Seungmee Jung","orcid":"0000-0003-2660-7663","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:52:00.885532Z","pmid":"41407331","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}