KLF4
KLF4 (Krüppel-like factor 4) is a transcription factor implicated in the regulation of epithelial integrity, endothelial function, immune-cell state, vascular smooth-muscle phenotype, and cellular responses to oxidative stress and ferroptosis.
KLF4 (Krüppel-like factor 4) is a transcription factor implicated in the regulation of epithelial integrity, endothelial function, immune-cell state, vascular smooth-muscle phenotype, and cellular responses to oxidative stress and ferroptosis. In the studies summarized here, KLF4 functions as a context-dependent regulator: its activity is associated with transcription of tight-junction genes, mitochondrial respiratory-chain programs, and signaling pathways involving β-catenin, SIRT3, and glutathione peroxidase 4 (GPX4).
KLF4 has been investigated as a target in cancer progression and immunity, aging-related neurovascular dysfunction, cardiovascular disease, diabetic nephropathy, and cellular therapies. The reported work uses approaches including RNA sequencing, CRISPR-Cas methods, chromatin immunoprecipitation, luciferase and RNA immunoprecipitation assays, western blotting, and functional cell assays. Collectively, these studies place KLF4 at the intersection of epithelial barrier regulation, the blood–brain barrier, oxidative stress, ferroptosis, tumor microenvironment signaling, and CAR-T-cell function.
Rebuilt from PubMed 18 Sept 2026 · no new papers today
Where the papers sit
10 papers study klf4 directly. The themes below are drawn from those 10. 2 new directions follow.
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Cellular Stress, Immunity and Metabolism : Ferroptosis, vascular remodeling, CAR-T exhaustion and metabolic disease appear as separate KLF4-linked contexts, with no shared disease mechanism or therapeutic direction. 5 papers · 50%
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Cancer Progression and Immunity : KLF4 loss is linked to immune evasion and poor anti-PD-1 response, while AT1 blockade restores tight junctions and limits gastric metastasis. Valproic acid plus zebularine targets KLF4/β-catenin signaling, supporting pathway-directed treatment. 3 papers · 30%
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Neurovascular Aging and Ferroptosis : Endothelial KLF4 depletion is associated with blood–brain barrier dysfunction and neuropsychiatric impairment. Repairing mitochondrial function through the ATP11B-YAP axis and inhibiting neuronal ferroptosis emerge as strategies against age-related cognitive decline. 2 papers · 20%
KLF4 can drive a chemoresistant tumor-cell state rather than suppressing malignancy
Lung squamous cell carcinoma models in “A Barrier Betrayed” show that, instead of merely supporting epithelial barrier integrity or antitumor responses as in the other abstracts, KLF4 drives KRT13 expression in slow-cycling hillock-like tumor cells associated with platinum resistance. This places KLF4 in a tumor-intrinsic, resistance-promoting role and suggests that its inhibition, rather than induction, may be therapeutically relevant in this subtype 42740576Sep.
KLF4 can directly preserve CAR T-cell function by preventing exhaustion
CAR T cells used against refractory or relapsed lymphoma and leukemia are shown to gain antitumor potency when KLF4 is overexpressed, through prevention of the exhaustion that limits persistence and durability. Unlike the abstracts that assign KLF4 roles in tumor cells, epithelial barriers, or vascular homeostasis, this finding makes KLF4 an intrinsic regulator of engineered T-cell fitness and a potential CAR T-cell engineering target 42161404May.
Recent Findings on KLF4
Context-Dependent Cell Regulation: KLF4 changes cell states according to tissue context, protecting renal tubular epithelial cells while promoting specialized tumor and vascular phenotypes. In hyperglycemic HK-2 cells, miR-145-5p suppresses KLF4, weakening the SIRT3/GPX4 antioxidant axis, reducing glutathione and GPX4 activity, and aggravating ferroptosis 42494277Jul. Microbial pantothenic acid instead supports PANK2/3-dependent CoA/acetyl-CoA metabolism and KLF4-associated differentiation programs, preserving gut barrier integrity and metabolic function 42385714Jul. KLF4 also drives KRT13 expression in slow-cycling hillock-like lung squamous cell carcinoma cells, which correlate with therapeutic targets and platinum resistance, while endothelial exosomal MSTRG.12883.2 relieves miR-632 repression of KLF4 and promotes ox-LDL-induced vascular smooth muscle cell switching 42740576Sep42107690May. KLF4 overexpression in CAR-T cells further enhances antitumor potency by preventing exhaustion 42161404May.
Cancer Progression and Immunity: KLF4 loss promotes cancer immune evasion and epithelial disorganization, whereas pharmacological or receptor-directed approaches can restore KLF4-linked antitumor functions. In esophageal cancer, reduced KLF4 limits chromatin accessibility and enhanceosome formation at MHC class I loci, diminishing CD8⁺ T-cell infiltration and impairing anti-PD-1 therapy; pharmacological KLF4 induction reverses these effects in mouse models 42493491Jul. AT1R blockade restores KLF4-dependent transcription of CLDN1, CLDN3, CLDN4, and TJP1, thereby stabilizing tight junctions and limiting gastric cancer growth and metastasis 42081962May. Valproic acid and Zebularine synergistically inhibit colon cancer cell proliferation while altering KLF4 and CTNNB1 expression, but the reported KLF4 direction varies between assays, with both induction and later reduction described 42224286Jun.
Neurovascular Aging and Ferroptosis: Endothelial KLF4 depletion accelerates blood–brain barrier failure, neurovascular dysfunction, neuroinflammation, neurodegeneration, and cognitive impairment in middle-aged mice. Single-cell RNA sequencing links KLF4 loss to dysregulated immune-response and barrier-related genes, while chromatin-level effects implicate KLF4 in constraining proinflammatory and senescence programs 42313933Jun. ATP11B deficiency increases Fe²⁺ transfer to hippocampal neurons, activates Hippo signaling, disrupts mitochondrial respiration and quality control, and induces neuronal ferroptosis through altered KLF4 accessibility at mitochondrial respiratory-chain genes 42002550Apr. The ATP11B-YAP axis and lactate-mediated TEAD-YAP histone lactylation of Acsl4, Trp53, and Cdkn1a are emerging targets for correcting iron homeostasis, mitochondrial dysfunction, and age-related cognitive decline 42002550Apr.
Written from 10 PubMed abstracts, each one cited by PMID above. Published: 2026-09-10. Last written: 2026-09-17 by GPT. Drafted by language models from published abstracts; not medical advice.