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Through stress-signal and metabolic integration, ATF family members coordinate macrophage functions such as inflammatory responses, glucose‑lipid metabolism, adaptation to cellular stress, autophagy‑apoptosis balance and senescence. The review synthesizes how ATFs govern development, survival, migration, phagocytosis, activation/cytokine secretion, polarization and metabolic reprogramming, and evaluates therapeutic feasibility for ATF-targeted 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Orchestrators of macrophage biology in pathological settings (Review)  \nYUE‑CHEN LIU 1 , JIA‑WEI ZHAO 1 , XIONG‑TAO YUE 1 , QI‑JIE CHEN 1 , SHAN‑JIE RONG 1 , SHI‑WEI LIU2 , FEI SUN3,4 , CHUN‑LIANG YANG3 and CONG‑YI WANG2‑4  \n1  \nDepartment of Respiratory and Critical Care Medicine, The Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430100, P.R. China;  \n2  \nTongji Shanxi Hospital, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Third Hospital of Shanxi Medical University,  \n3  \nThe Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province, Taiyuan, Shanxi 030032, P.R. China; Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, P.O. Box 34110, Doha, Qatar; 4The Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital Research Building, Wuhan, Hubei 430100, P.R. China  \nReceived August 21, 2025; Accepted November 27, 2025  \nDOI: 10.3892/ijmm.2025.5720  \nAbstract. Macrophages, an essential component of the innate immune system, exhibit remarkable plasticity and functional heterogeneity governed by the intricate transcriptional regulatory networks. Activating transcription factors (ATFs) have recently been recognized to modulate multiple signaling pathways, including the MAPK cascades, endoplasmic reticulum stress response and NF‑κB signaling, thereby regulating macrophage biological processes such as inflammatory response, glucose‑lipid metabolism, cellular stress adaptation, autophagy‑apoptosis balance and senescence. By integrating stress signals and metabolic cues, ATF family members construct a sophisticated  \nCorrespondence to: Dr Cong‑Yi Wang or Dr Chun‑Liang Yang, Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, P.O. Box 34110, Doha, Qatar  \nE‑mail: [cwang@hbku.edu.qa](cwang@hbku.edu.qa)  \nE‑mail: [cyang@hbku.edu.qa](cyang@hbku.edu.qa)  \nAbbreviations: ATFs, activating transcription factors; ATM, adipose tissue macrophage; AD, Alzheimer's disease; bZIP, basic leucine zipper; CRE, cAMP response element; C/EBP, CCAAT/enhancer‑binding protein; ER, endoplasmic reticulum; gMac, gut‑resident macrophages; HSCs, hematopoietic stem cells; HO‑1, heme oxygenase‑1; IRI, ischemia‑reperfusion injury; LPS, lipopolysaccharide; LXR, liver X receptor; M‑CSF, macrophage colony‑stimulating factor; NO, nitric oxide; oxLDL, oxidized low‑density lipoprotein; PGN, peptidoglycan; PAS, placental accreta spectrum; PROTAC, proteolysis‑targeting chimera; RTECs, renal tubular epithelial cells; SMCs, smooth muscle cells; SIRS, systemic inflammatory response syndrome; TLR, Toll‑like receptor; UPR, unfolded protein response  \nKey words: activating transcription factors, macrophage, metabolic disorders, chronic inflammation, cytokines, targeted therapy  \nregulatory network implicated in the pathogenesis of infectious and inflammatory diseases, metabolic disorders, malignancies and neurodegenerative diseases. Therefore, targeted modula‑ tions of ATFs or their associated pathways are considered to be capable of precisely regulating macrophage anti‑inflammatory function, metabolic activity and tissue repair capacity in disease settings. Recent technological advances, such as specific targeted delivery systems and gene‑editing strategies, offer promising avenues for the spatiotemporal ATF‑targeting interventions in macrophages, which is critical for improving therapeutic efficacy and safety. The present review systematically summarized recent advances in the understanding of ATF‑mediated regulation of macrophage development, survival, migration, phagocytosis, activation/cytokine secretion, along with polarization and meta‑ bolic reprogramming. It also elucidated the pathophysiologica","cbCaiiN1VfKqbG9B","https://ap.wps.com/l/cbCaiiN1VfKqbG9B","pdf",3553639,28,"English","# 1. Introduction\n# 2. ATFs are pivotal signaling hubs\n# 3. ATFs in macrophage development and survival\n# 4. ATFs in macrophage chemotaxis and phagocytosis\n# 5. ATFs in macrophage activation and cytokine secretion\n# 6. ATFs in macrophage polarization and phenotypic plasticity\n# 7. ATFs in macrophage-associated diseases\n# 8. Targeting ATFs in macrophages could be a potential therapeutic strategy\n# 9. Conclusions and perspectives","[{\"question\":\"What roles do activating transcription factors (ATFs) play in macrophage biology?\",\"answer\":\"ATFs modulate several signaling pathways, including MAPK cascades, ER stress response and NF‑κB signaling, thereby shaping macrophage biological processes such as inflammation and stress adaptation.\"},{\"question\":\"Which macrophage functions are highlighted as being regulated by ATFs?\",\"answer\":\"The review covers regulation of macrophage development, survival, migration, phagocytosis, activation/cytokine secretion, polarization and metabolic reprogramming, and connects these to disease mechanisms.\"},{\"question\":\"How could ATF-targeted interventions be used therapeutically?\",\"answer\":\"Targeted modulation of ATFs or their associated pathways is proposed to precisely control macrophage anti-inflammatory function, metabolic activity and tissue repair capacity, supported by emerging targeted delivery and gene-editing strategies.\"}]","Activating transcription factors: Orchestrators of macrophage biology in pathological settings - Review | PDF",1790675232,71]