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Transcription factor Krüppel‐like factor 5 (KLF5) is a member of the Krüppel‐like factors’ (KLFs) family. KLF5 regulates a number of cellular functions, such as apoptosis, proliferation and differentiation. Therefore, KLF5 can play a role in many diseases, including, cancer, cardiovascular disease and gastrointestinal disorders. An important role for KLF5 in the kidney was recently reported, such that KLF5 regulated podocyte apoptosis, renal cell proliferation, tubulointerstitial inflammation and renal fibrosis. In this review, we have summarized the available information in the literature with a brief description on how transcriptional, post‐transcriptional and post‐translational modifications of KLF5 modulate its function in a variety of organs including the kidney with a focus of its importance on the pathogenesis of various kidney diseases. Furthermore, we also have outlined the current and possible mechanisms of KLF5 activation in kidney diseases. These studies suggest a need for more systemic investigations, particularly for generation of animal models with renal cell‐specific deletion or overexpression of KLF5 gene to examine direct contributions of KLF5 to various kidney diseases. This will promote further experimentation in the development of therapies to prevent or treat various kidney diseases.

Juvenile hormones and the genetic interaction between the transcription factors Krüppel homologue 1 ( Kr-h1 ) and Broad ( Br ) regulate the transformation of insects from immature to adult forms in both types of metamorphosis (holometaboly with a pupal stage versus hemimetaboly with no pupal stage); however, knowledge about the exact instar in which this occurs is limited. Using the hemimetabolous cricket Gryllus bimaculatus ( Gb ), we demonstrate that a genetic interaction occurs among Gb ′ Kr-h1 , Gb ′ Br and the adult-specifier transcription factor Gb ′ E93 from the sixth to final (eighth) nymphal instar. Gb ′ Kr-h1 and Gb ′ Br mRNAs were strongly expressed in the abdominal tissues of sixth instar nymphs, with precocious adult moults being induced by Gb ′ Kr-h1 or Gb ′ Br knockdown in the sixth instar. The depletion of Gb ′ Kr-h1 or Gb ′ Br upregulates Gb ′ E93 in the sixth instar. By contrast, Gb ′ E93 knockdown at the sixth instar prevents nymphs transitioning to adults, instead producing supernumerary nymphs. Gb ′ E93 also represses Gb ′ Kr-h1 and Gb ′ Br expression in the penultimate nymphal instar, demonstrating its important role in adult differentiation. Our results suggest that the regulatory mechanisms underlying the pupal transition in holometabolous insects are evolutionarily conserved in hemimetabolous G . bimaculatus , with the penultimate and final nymphal periods being equivalent to the pupal stage. This article is part of the theme issue ‘The evolution of complete metamorphosis’.

Krüppel‐like Factor 7 (KLF7) is a zinc finger transcription factor that has a critical role in cellular differentiation, tumorigenesis, and regeneration. Mutations in Klf7 are associated with autism spectrum disorder, which is characterized by neurodevelopmental delay and intellectual disability. Here we show that KLF7 regulates neurogenesis and neuronal migration during mouse cortical development. Conditional depletion of KLF7 in neural progenitor cells resulted in agenesis of the corpus callosum, defects in neurogenesis, and impaired neuronal migration in the neocortex. Transcriptomic profiling analysis indicated that KLF7 regulates a cohort of genes involved in neuronal differentiation and migration, including p21 and Rac3. These findings provide insights into our understanding of the potential mechanisms underlying neurological defects associated with Klf7 mutations. Conditional depletion of KLF7 in neural progenitor cells resulted in agenesis of the corpus callosum and impaired neuronal migration in the mouse neocortex through regulation of p21 and Rac3.

Krüppel‐like factors (KLFs) are crucial in the development of bone disease. They are a family of zinc finger transcription factors that are unusual in containing three highly conserved zinc finger structural domains interacting with DNA. It has been discovered that it engages in various cell functions, including proliferation, apoptosis, autophagy, stemness, invasion and migration, and is crucial for the development of human tissues. In recent years, the role of KLFs in bone physiology and pathology has received adequate attention. In addition to regulating the normal growth and development of the musculoskeletal system, KLFs participate in the pathological process of the bones and joints and are intimately linked to several skeletal illnesses, such as osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis (OP) and osteosarcoma (OS). Consequently, targeting KLFs has emerged as a promising therapeutic approach for an array of bone disorders. In this review, we summarize the current literature on the importance of KLFs in the emergence and regulation of bone illnesses, with a particular emphasis on the pertinent mechanisms by which KLFs regulate skeletal diseases. We also discuss the need for KLFs‐based medication‐targeted treatment. These endeavours offer new perspectives on the use of KLFs in bone disorders and provide prognostic biomarkers, therapeutic targets and possible drug candidates for bone diseases.

Developmental, genetic and endocrine data from diverse taxa provide insight into the evolution of insect metamorphosis. We equate the larva–pupa–adult of the Holometabola to the pronymph–nymph–adult of hemimetabolous insects. The hemimetabolous pronymph is a cryptic embryonic stage with unique endocrinology and behavioural modifications that probably served as preadaptations for the larva. It develops in the absence of juvenile hormone (JH) as embryonic primordia undergo patterning and morphogenesis, the processes that were arrested for the evolution of the larva. Embryonic JH then drives tissue differentiation and nymph formation. Experimental treatment of pronymphs with JH terminates patterning and induces differentiation, mimicking the processes that occurred during the evolution of the larva. Unpatterned portions of primordia persist in the larva, becoming imaginal discs that form pupal and adult structures. Key transcription factors are associated with the holometabolous life stages: Krüppel-homolog 1 ( Kr-h1 ) in the larva, broad in the pupa and E93 in the adult. Kr-h1 mediates JH action and is found whenever JH acts, while the other two genes direct the formation of their corresponding stages. In hemimetabolous forms, the pronymph has low Broad expression, followed by Broad expression through the nymphal moults, then a switch to E93 to form the adult. This article is part of the theme issue ‘The evolution of complete metamorphosis’.

Previous studies have shown that podocyte injury is involved in the development of proteinuria in rats under hypobaric hypoxia conditions. Prolyl hydroxylase inhibitors (PHIs) may reduce proteinuria. This study aimed to further investigate whether the protective effects of hypoxia‐inducible factor 1α (HIF1α) on podocyte injury induced by hypobaric hypoxia are related to Krüppel‐like factor 4 (KLF4). Rats were housed in a low‐pressure oxygen chamber to simulate a high‐altitude environment (5000 m), and a PHI was intraperitoneally injected. Urinary protein electrophoresis was performed and the morphology of the podocytes was observed by electron microscopy. Rat podocytes were cultured under 1% O2, and siRNA was used to interfere with KLF4 expression. The protein expression levels of HIF1α, KLF4, CD2‐associated protein (CD2AP) and nephrin were determined by western blotting. Compared with those in the experimental group, the rats in the intervention group on day 14 had lower urinary protein levels, increased protein expression levels of CD2AP and nephrin, and reduced podocyte injury. The results of in vitro experiments showed that the protein expression levels of KLF4, CD2AP and nephrin were greater in the PHI intervention group and lower in the HIF1α inhibitors group than in the low‐oxygen group. The protein expression of CD2AP and nephrin in the siKLF4‐transfected podocytes treated with PHI and HIF1α inhibitors did not differ significantly from that in the low‐oxygen group. HIF1α may be involved in reducing progressive high‐altitude proteinuria by regulating KLF4 expression and contributing to the repair of podocyte injury induced by hypobaric hypoxia. What is the central question of this study? Podocyte injury is involved in the development of proteinuria in rats under simulated high‐altitude environments and prolyl‐hydroxylase inhibitors (PHI) may have a potential role in reducing proteinuria: what are the effects of PHIs on podocytes and what are the mechanisms? What is the main finding and its importance? PHIs may have a potential role in reducing proteinuria by upregulating local hypoxia‐inducible factor 1α (HIF1α) expression in the kidney to alleviate podocyte injury. HIF1α plays a potential role in regulating Krüppel‐like factor 4 expression and contributing to the repair of podocyte injury induced by hypobaric hypoxia.

Krüppel-like factor 4 (KLF4) is a transcription factor which functions as a tumor suppressor or an oncogene in numerous types of solid tumors. However, its expression levels and function in perihilar cholangiocarcinoma (pCCA) have yet to be elucidated. In the present study, in order to investigate its roles in pCCA, reverse transcription-quantitative PCR (RT-qPCR), western blot analysis and immunohistochemistry were used to detect KLF4 expression in pCCA. The Chi-squared test was used to analyze the associations between KLF4 and the clinicopathological features of patients with pCCA. Univariate and multivariate analyses were subsequently used to analyze the prognostic significance of KLF4. The tumor suppression of KLF4 was investigated for the purposes of illustrating its biological function both in vitro and in vivo. Furthermore, the association between KLF4 and growth/differentiation factor 15 (GDF15) was determined using pCCA tissue microarray (TMA) analysis and RT-qPCR. The underlying molecular mechanisms between KLF4 and GDF15 were subsequently investigated in vitro. In pCCA tissues, KLF4 was found to be downregulated, and this was negatively associated with the histological grade and tumor size. The knockdown of KLF4 was also found to be a prognostic indicator of the poorer survival of patients with pCCA. Based on in vitro and in vivo analyses, KLF4 was found to suppress tumor progression and induce cell apoptosis. Furthermore, it was found that KLF4 executed its tumor suppressive effects via the regulation of the GDF15/AKT signaling pathway. Taken together, the findings of the present study demonstrate that KLF4 may be considered as an independent biomarker of a favorable prognosis of patients with pCCA, and the KLF4/GDF15/AKT signaling pathway may potentially be a novel molecular therapeutic target for patients with pCCA.

Krüppel‐like factor 15 (KLF15) is a transcription factor contributing to the pathophysiology of multiple diseases, including metabolic syndromes. It is 416 residues long, with a C2H2‐type zinc finger (ZnF) domain that binds to GC‐rich regions regulating transcription. The role of KLF15 in glucogenesis and glucose level maintenance is well established. However, the DNA interaction mechanism at the atomic level remains unresolved. Here, we utilised computational structural biology tools to address this knowledge gap. The KLF15 ZnF–domain interacting with DNA was modelled with AlphaFold 3.0. Alanine substitution of the KLF15 ZnF domain–DNA complex revealed that residues K334A, R334A, Y332A and R392A significantly affect the binding affinities (ΔΔG) to DNA. To understand the conformational stability and dynamics of the KLF15 ZnF–domain complexes, 100‐ns molecular dynamics simulations were performed. Additionally, molecular mechanics‐generalised Born (MM/GBSA) surface area was utilised to calculate total binding energies. The binding energies of the wild‐type KLF15 ZnF domain (−94.0 ± 0.17 kcal/mol) demonstrated a more robust binding affinity to DNA than K334A (−30.4 ± 0.35 kcal/mol), R344A (−42.8 ± 0.37 kcal/mol), Y332A (−47.7 ± 0.42 kcal/mol) and R392A (−30.8 ± 0.30 kcal/mol). The findings highlighted the unstable dynamics of the alinine substituted resdiues that consequently reduce the binding free energy compared to the wild‐type KLF15 ZnF domain. In conclusion, the four identified residues are essential to recognise KLF15 ZnF DNA binding and can be considered potential hotspots for the therapeutics development for type 2 diabetes.

Krüppel-like factor (KLF) 5 has garnered increasing interest in cancer research, as a zinc finger transcription factor integral to the regulation of cellular growth and division through gene transcription control. Initially investigated for its role in transcriptional regulation during normal tissue development, KLF5 was subsequently identified as a driver of cancer progression upon aberrant activation of its transcriptional activity. This functional dichotomy in transcriptional regulation has considerably enhanced the current understanding of the significance of KLF5 in human cancer. The dysregulation of such critical transcription factors has been shown to be closely linked with gynecological tumors, including cervical, ovarian and endometrial cancer. However, the specific regulatory mechanisms by which KLF5 influences the initiation and progression of gynecological tumors remains to be elucidated. The present review highlights the role of the KLF5 transcriptional regulatory network in the pathogenesis of gynecological tumors and its potential as a therapeutic target.

Osteosarcoma, the most common bone malignancy, has a high morbidity rate and poor prognosis. Krüppel‐like factor 5 (KLF5) is a key transcriptional regulator of cellular proliferation whose overexpression is observed in osteosarcoma cell lines (U2OS, 143B, MG63 and SAOS2). ML264, a small‐molecule inhibitor of KLF5, exerts antiproliferative effects in colorectal cancer; however, its function in osteosarcoma remains unknown. Here, we explored the possible antitumour effects of ML264 on 143B and U2OS cell lines and murine tumour xenograft model. ML264 suppressed proliferation and clonogenic ability of osteosarcoma cells in a dose‐dependent manner. Moreover, ML264 induced G0/G1 cell cycle arrest, with no influence on apoptosis, and inhibited the migratory and invasive abilities of osteosarcoma cells, as demonstrated by wound‐healing and Transwell assays. Exposure to ML264 reduced the mRNA and protein levels of molecules associated with epithelial‐mesenchymal transition phenotype, including N‐cadherin, vimentin, Snail, matrix metalloproteinase (MMP) 9 and MMP13. Inhibition of signal transducer and activator of transcription (STAT) 3 phosphorylation and Wnt signalling was also observed. In the murine model of osteosarcoma, tumour growth was efficiently suppressed following a 10‐day treatment with ML264. Collectively, our findings demonstrate the potential value of ML264 as a novel anticancer drug for osteosarcoma.