{"doi":"10.1111/acel.70038","title":"<scp>HLH</scp> ‐30/ <scp>TFEB</scp> Rewires the Chaperone Network to Promote Proteostasis Upon Perturbations to the Coenzyme A and Iron–Sulfur Cluster Biosynthesis Pathways","abstract":"The maintenance of a properly folded proteome is critical for cellular function and organismal health, and its age-dependent collapse is associated with a wide range of diseases. Here, we find that despite the central role of Coenzyme A as a molecular cofactor in hundreds of cellular reactions, inhibition of the first and rate-limiting step in CoA biosynthesis can be beneficial and promote proteostasis. Impairment of the cytosolic iron-sulfur cluster formation pathway, which depends on Coenzyme A, similarly promotes proteostasis and acts in the same pathway. Proteostasis improvement by interference with the Coenzyme A/iron-sulfur cluster biosynthesis pathways is dependent on the conserved HLH-30/TFEB transcription factor. Strikingly, under these conditions, HLH-30 promotes proteostasis by potentiating the expression of select chaperone genes, providing a chaperone-mediated proteostasis shield, rather than by its established role as an autophagy and lysosome biogenesis-promoting factor. This reflects the versatile nature of this conserved transcription factor, which can transcriptionally activate a wide range of protein quality control mechanisms, including chaperones and stress response genes alongside autophagy and lysosome biogenesis genes. These results highlight TFEB as a key proteostasis-promoting transcription factor and underscore it and its upstream regulators as potential therapeutic targets in proteostasis-related diseases.","journal":"Aging Cell","year":2025,"id":533615,"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":0.947,"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":1415818,"name":"Dror Michael Solomon","orcid":null,"position":1,"is_corresponding":false},{"id":587521,"name":"Mor Levi‐Ferber","orcid":null,"position":2,"is_corresponding":false},{"id":945502,"name":"Henrik von Chrzanowski","orcid":null,"position":3,"is_corresponding":false},{"id":917919,"name":"Mohammad Khaled Atrash","orcid":null,"position":4,"is_corresponding":false},{"id":1415819,"name":"Barak Nakar","orcid":null,"position":5,"is_corresponding":false},{"id":624562,"name":"Matan Y. Avivi","orcid":null,"position":6,"is_corresponding":false},{"id":1181477,"name":"Hagit Hauschner","orcid":"0000-0001-7198-5730","position":7,"is_corresponding":false},{"id":1415820,"name":"Aviya Swisa","orcid":null,"position":8,"is_corresponding":false},{"id":707540,"name":"Alicia Meléndez","orcid":"0000-0002-1362-7705","position":9,"is_corresponding":false},{"id":516137,"name":"Yaron Shav‐Tal","orcid":"0000-0002-8017-948X","position":10,"is_corresponding":false},{"id":587026,"name":"Sivan Henis‐Korenblit","orcid":"0000-0001-8023-6336","position":11,"is_corresponding":false},{"id":587023,"name":"Rewayd Shalash","orcid":"0000-0002-7033-0940","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T02:51:32.301795Z","pmid":"40304211","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":[]}