Role of peroxisomes in the pathogenesis and therapy of renal fibrosis.

Renal fibrosis is a pathological consequence of end-stage chronic kidney disease, driven by factors such as oxidative stress, dysregulated fatty acid metabolism, extracellular matrix (ECM) imbalance, and epithelial-to-mesenchymal transition. Peroxisomes play a critical role in fatty acid β-oxidation and the scavenging of reactive oxygen species, interacting closely with mitochondrial functions. Nonetheless, current research often prioritizes the mitochondrial influence on renal fibrosis, often overlooking the contribution of peroxisomes.

Pharmacological targeting of AMPK to restore glucose and fatty acid metabolism homeostasis attenuates transplanted kidney fibrosis.

Chronic fibrosis often occurs in transplanted kidneys, leading to progressive functional decline. The underlying mechanisms may involve disruption in the metabolism of renal tubular epithelial cells. The liver kinase B1 (LKB1)-AMPK pathway is a pivotal regulatory hub for glucose and fatty acid metabolism and may play a role in transplanted kidney fibrosis, but it has not been reported.

The role of macrophages in fibrosis of chronic kidney disease.

Macrophages are widely distributed throughout various tissues of the body, and mounting evidence suggests their involvement in regulating the tissue microenvironment, thereby influencing disease onset and progression through direct or indirect actions. In chronic kidney disease (CKD), disturbances in renal functional homeostasis lead to inflammatory cell infiltration, tubular expansion, glomerular atrophy, and subsequent renal fibrosis. Macrophages play a pivotal role in this pathological process.

ACOX1 deficiency-induced lipid metabolic disorder facilitates chronic interstitial fibrosis development in renal allografts.

Chronic interstitial fibrosis presents a significant challenge to the long-term survival of transplanted kidneys. Our research has shown that reduced expression of acyl-coenzyme A oxidase 1 (ACOX1), which is the rate-limiting enzyme in the peroxisomal fatty acid β-oxidation pathway, contributes to the development of fibrosis in renal allografts. ACOX1 deficiency leads to lipid accumulation and excessive oxidation of polyunsaturated fatty acids (PUFAs), which mediate epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) reorganization respectively, thus causing fibrosis in renal allografts.

Peroxisome proliferator-activated receptors: A key link between lipid metabolism and cancer progression.

Lipids represent the essential components of membranes, serve as fuels for high-energy processes, and play crucial roles in signaling and cellular function. One of the key hallmarks of cancer is the reprogramming of metabolic pathways, especially abnormal lipid metabolism. Alterations in lipid uptake, lipid desaturation, de novo lipogenesis, lipid droplets, and fatty acid oxidation in cancer cells all contribute to cell survival in a changing microenvironment by regulating feedforward oncogenic signals, key oncogenic functions, oxidative and other stresses, immune responses, or intercellular communication.

Targeted changes in blood lipids improves fibrosis in renal allografts.

Background: Chronic interstitial fibrosis is the primary barrier against the long-term survival of transplanted kidneys. Extending the lifespan of allografts is vital for ensuring the long-term health of patients undergoing kidney transplants. However, few targets and their clinical applications have been identified.

Human papillomavirus type 16 E6 promotes cervical cancer proliferation by upregulating transketolase enzymatic activity through the activation of protein kinase B.

Over 99% of precancerous cervical lesions are associated with human papillomavirus (HPV) infection, with HPV types 16 and 18 (especially type 16) found in over 70% of cervical cancer cases globally. E6, a critical HPV gene, triggers malignant proliferation by degrading p53; however, this mechanism alone cannot fully explain the oncogenic effects of HPV16 E6. Therefore, we aimed to investigate new targets of HPV oncogenic mechanisms.

The connection between tricarboxylic acid cycle enzyme mutations and pseudohypoxic signaling in pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells, holding significant clinical importance due to their capacity for excessive catecholamine secretion and associated cardiovascular complications. Roughly 80% of cases are associated with genetic mutations. Based on the functionality of these mutated genes, PPGLs can be categorized into distinct molecular clusters: the pseudohypoxia signaling cluster (Cluster-1), the kinase signaling cluster (Cluster-2), and the WNT signaling cluster (Cluster-3).

Regulatory mechanisms of the cAMP-responsive element binding protein 3 (CREB3) family in cancers.

The CREB3 family of proteins, encompassing CREB3 and its four homologs (CREB3L1, CREB3L2, CREB3L3, and CREB3L4), exerts pivotal control over cellular protein metabolism in response to unfolded protein reactions. Under conditions of endoplasmic reticulum stress, activation of the CREB3 family occurs through regulated intramembrane proteolysis within the endoplasmic reticulum membrane. Perturbations in the function and expression of the CREB3 family have been closely associated with the development of diverse diseases, with a particular emphasis on cancer.

Recent findings in the regulation of G6PD and its role in diseases.

Glucose-6-phosphate dehydrogenase (G6PD) is the only rate-limiting enzyme in the pentose phosphate pathway (PPP). Rapidly proliferating cells require metabolites from PPP to synthesize ribonucleotides and maintain intracellular redox homeostasis. G6PD expression can be abnormally elevated in a variety of cancers.

The role of transketolase in human cancer progression and therapy.

Transketolase (TKT) is an enzyme that is ubiquitously expressed in all living organisms and has been identified as an important regulator of cancer. Recent studies have shown that the TKT family includes the TKT gene and two TKT-like (TKTL) genes; TKTL1 and TKTL2. TKT and TKTL1 have been reported to be involved in the regulation of multiple cancer-related events, such as cancer cell proliferation, metastasis, invasion, epithelial-mesenchymal transition, chemoradiotherapy resistance, and patient survival and prognosis.

The role of liver kinase B1 in tumor progression through regulation of lipid metabolism.

The somatic mutation of liver kinase B1 (LKB1) has been implicated in various tumors, which is reflected in the survival, proliferation, and metastasis of tumor cells. However, the regulation of LKB1 in lipid metabolism, a process that is involved in tumor progression is not completely clear. We conclude that LKB1 deficiency results in abnormal expression and activation of multiple molecules related to lipid metabolism which locate downstream of AMP-activated protein kinase (AMPK) or salt-induced kinase (SIK).

LKB1 deficiency-induced metabolic reprogramming in tumorigenesis and non-neoplastic diseases.

Background: Live kinase B1 (LKB1) is a tumor suppressor that is mutated in Peutz-Jeghers syndrome (PJS) and a variety of cancers. Lkb1 encodes serine-threonine kinase (STK) 11 that activates AMP-activated protein kinase (AMPK) and its 13 superfamily members, regulating multiple biological processes, such as cell polarity, cell cycle arrest, embryo development, apoptosis, and bioenergetics metabolism. Increasing evidence has highlighted that deficiency of LKB1 in cancer cells induces extensive metabolic alterations that promote tumorigenesis and development.

Fenofibrate Improved Interstitial Fibrosis of Renal Allograft through Inhibited Epithelial-Mesenchymal Transition Induced by Oxidative Stress.

The best treatment for end-stage renal disease is renal transplantation. However, it is often difficult to maintain a renal allograft healthy for a long time following transplantation. Interstitial fibrosis and tubular atrophy (IF/TA) are significant histopathologic characteristics of a compromised renal allograft.

PARP-1 inhibitors sensitize HNSCC cells to APR-246 by inactivation of thioredoxin reductase 1 (TrxR1) and promotion of ROS accumulation.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Mutations of TP53 may reach 70% - 85% in HNSCC patients without human papillomavirus (HPV) infection. Recurrence rate remains particularly high for HNSCC patients with mutations in the TP53 gene although patients are responsive to surgery, irradiation, and chemotherapy early in the treatment.

Piperlongumine and p53-reactivator APR-246 selectively induce cell death in HNSCC by targeting GSTP1.

TP53 mutations frequently occur in head and neck squamous cell carcinoma (HNSCC) patients without human papillomavirus infection. The recurrence rate for these patients is distinctly high. It has been actively explored to identify agents that target TP53 mutations and restore wild-type (WT) TP53 activities in HNSCC.