Jiaying Fu

Systemic chronic inflammation (SCI) due to intrinsic immune over-activation is an important factor in the development of many noninfectious chronic diseases, such as neurodegenerative diseases and diabetes mellitus. Among these immune responses, macrophages are extensively involved in the regulation of inflammatory responses by virtue of their polarization plasticity; thus, dysregulation of macrophage polarization direction is one of the potential causes of the generation and maintenance of SCI. High-temperature demand protein A2 (HtrA2/Omi) is an important regulator of mitochondrial quality control, not only participating in the degradation of mis-accumulated proteins in the mitochondrial unfolded protein response (UPRmt) to maintain normal mitochondrial function through its enzymatic activity, but also participating in the regulation of mitochondrial dynamics-related protein interactions to maintain mitochondrial morphology. Recent studies have also reported the involvement of HtrA2/Omi as a novel inflammatory mediator in the regulation of the inflammatory response. HtrA2/Omi regulates the inflammatory response in BMDM by controlling TRAF2 stabilization in a collagen-induced arthritis mouse model; the lack of HtrA2 ameliorates pro-inflammatory cytokine expression in macrophages. In this review, we summarize the mechanisms by which HtrA2/Omi proteins are involved in macrophage polarization remodeling by influencing macrophage energy metabolism reprogramming through the regulation of inflammatory signaling pathways and mitochondrial quality control, elucidating the roles played by HtrA2/Omi proteins in inflammatory responses. In conclusion, interfering with HtrA2/Omi may become an important entry point for regulating macrophage polarization, providing new research space for developing HtrA2/Omi-based therapies for SCI.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and, with increasing research on the tumor immune microenvironment (TIME), the immunosuppressive micro-environment of HCC hampers further application of immunotherapy, even though immunotherapy can provide survival benefits to patients with advanced liver cancer. Current studies suggest that polyamine metabolism is not only a key metabolic pathway for the formation of immunosuppressive phenotypes in tumor-associated macrophages (TAMs), but it is also profoundly involved in mitochondrial quality control signaling and the energy metabolism regulation process, so it is particularly important to further investigate the role of polyamine metabolism in the tumor microenvironment (TME). In this review, by summarizing the current research progress of key enzymes and substrates of the polyamine metabolic pathway in regulating TAMs and T cells, we propose that polyamine biosynthesis can intervene in the process of mitochondrial energy metabolism by affecting mitochondrial autophagy, which, in turn, regulates macrophage polarization and T cell differentiation. Polyamine metabolism may be a key target for the interactive dialog between HCC cells and immune cells such as TAMs, so interfering with polyamine metabolism may become an important entry point to break intercellular communication, providing new research space for developing polyamine metabolism-based therapy for HCC.

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. β-amyloid plaque (Aβ) deposition and hyperphosphorylated tau, as well as dysregulated energy metabolism in the brain, are key factors in the progression of AD. Many studies have observed abnormal iron accumulation in different regions of the AD brain, which is closely correlated with the clinical symptoms of AD; therefore, understanding the role of brain iron accumulation in the major pathological aspects of AD is critical for its treatment. This review discusses the main mechanisms and recent advances in the involvement of iron in the above pathological processes, including in iron-induced oxidative stress-dependent and non-dependent directions, summarizes the hypothesis that the iron-induced dysregulation of energy metabolism may be an initiating factor for AD, based on the available evidence, and further discusses the therapeutic perspectives of targeting iron.

Ovarian cancer is the most lethal gynecologic malignancy, and metastasis is the major cause of death in patients with ovarian cancer, which is regulated by the coordinated interplay of genetic and epigenetic mechanisms. Histone deacetylases (HDACs) are enzymes that can catalyze the deacetylation of histone and some non-histone proteins and that are involved in the regulation of a variety of biological processes via the regulation of gene transcription and the functions of non-histone proteins such as transcription factors and enzymes. Aberrant expressions of HDACs are common in ovarian cancer. Many studies have found that HDACs are involved in regulating a variety of events associated with ovarian cancer metastasis, including cell migration, invasion, and the epithelial–mesenchymal transformation. Herein, we provide a brief overview of ovarian cancer metastasis and the dysregulated expression of HDACs in ovarian cancer. In addition, we discuss the roles of HDACs in the regulation of ovarian cancer metastasis. Finally, we discuss the development of compounds that target HDACs and highlight their importance in the future of ovarian cancer therapy.

Cisplatin is a first-line clinical agent used for treating solid tumors. Cisplatin damages the DNA of tumor cells and induces the production of high levels of reactive oxygen species to achieve tumor killing. Tumor cells have evolved several ways to tolerate this damage. Extracellular vesicles (EVs) are an important mode of information transfer in tumor cells. EVs can be substantially activated under cisplatin treatment and mediate different responses of tumor cells under cisplatin treatment depending on their different cargoes. However, the mechanism of action of tumor-cell-derived EVs under cisplatin treatment and their potential cargoes are still unclear. This review considers recent advances in cisplatin-induced release of EVs from tumor cells, with the expectation of providing a new understanding of the mechanisms of cisplatin treatment and drug resistance, as well as strategies for the combined use of cisplatin and other drugs.

The metabolism and apoptosis of tumor cells are important factors that increase their sensitivity to chemotherapeutic drugs. p53 and cisplatin not only induce tumor cell apoptosis, but also regulate the tumor cell metabolism. The TP53-induced glycolysis and apoptosis regulator (TIGAR) can inhibit glycolysis and promote more glucose metabolism in the pentose phosphate pathway. We speculate that the regulation of the TIGAR by the combination therapy of p53 and cisplatin plays an important role in increasing the sensitivity of tumor cells to cisplatin. In this study, we found that the combined treatment of p53 and cisplatin was able to inhibit the mitochondrial function, promote mitochondrial pathway-induced apoptosis, and increase the sensitivity. Furthermore, the expression of the TIGAR was inhibited after a combined p53 and cisplatin treatment, the features of the TIGAR that regulate the pentose phosphate pathway were inhibited, the glucose flux shifted towards glycolysis, and the localization of the complex of the TIGAR and Hexokinase 2 (HK2) on the mitochondria was also reduced. Therefore, the combined treatment of p53 and cisplatin may modulate a glycolytic flux through the TIGAR, altering the cellular metabolic patterns while increasing apoptosis. Taken together, our findings reveal that the TIGAR may serve as a potential therapeutic target to increase the sensitivity of lung cancer A549 cells to cisplatin.

Obesity is one of the prominent global health issues, contributing to the growing prevalence of insulin resistance and type 2 diabetes. Chronic inflammation in adipose tissue is considered as a key risk factor for the development of insulin resistance and type 2 diabetes in obese individuals. Macrophages are the most abundant immune cells in adipose tissue and play an important role in adipose tissue inflammation. Mitochondria are critical for regulating macrophage polarization, differentiation, and survival. Changes to mitochondrial metabolism and physiology induced by extracellular signals may underlie the corresponding state of macrophage activation. Macrophage mitochondrial dysfunction is a key mediator of obesity-induced macrophage inflammatory response and subsequent systemic insulin resistance. Mitochondrial dysfunction drives the activation of the NLRP3 inflammasome, which induces the release of IL-1β. IL-1β leads to decreased insulin sensitivity of insulin target cells via paracrine signaling or infiltration into the systemic circulation. In this review, we discuss the new findings on how obesity induces macrophage mitochondrial dysfunction and how mitochondrial dysfunction induces NLRP3 inflammasome activation. We also summarize therapeutic approaches targeting mitochondria for the treatment of diabetes.

One of the most striking hallmarks shared by various neurodegenerative diseases, including Alzheimer’s disease (AD), is microglia-mediated neuroinflammation. The main pathological features of AD are extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles. The crosstalk between microglia and neurons helps maintain brain homeostasis, and the metabolic phenotype of microglia determines its polarizing phenotype. There are currently many research and development efforts to provide disease-modifying therapies for AD treatment. The main targets are Aβ and tau, but whether there is a causal relationship between neurodegenerative proteins, including Aβ oligomer and tau oligomer, and regulation of microglia metabolism in neuroinflammation is still controversial. Currently, the accumulation of Aβ and tau by exosomes or other means of propagation is proposed as a regulator in neurological disorders, leading to metabolic disorders of microglia that can play a key role in the regulation of immune cells. In this review, we propose that the accumulation of Aβ oligomer and tau oligomer can propagate to adjacent microglia through exosomes and change the neuroinflammatory microenvironment by microglia metabolic reprogramming. Clarifying the relationship between harmful proteins and microglia metabolism will help people to better understand the mechanism of crosstalk between neurons and microglia, and provide new ideas for the development of AD drugs.

Epithelial ovarian cancer has the highest mortality rate of all gynecological malignant tumors. Metastasis is the main cause of poor prognosis in patients with ovarian cancer. Epigenetic and protein post-translational modifications play important roles in tumor metastasis. As a member of class IIa histone deacetylases, histone deacetylase 9 (HDAC9) is involved in many biological processes by deacetylating histone and nonhistone proteins. However, its roles in ovarian cancer remain unclear. In this study, we found that patients with serous ovarian cancer with high expression of HDAC9 had poor prognoses. On the contrary, patients with non-serous ovarian cancer with high expression of HDAC9 had higher survival rates. In serous ovarian cancer, overexpressed HDAC9 may promote cell migration through the forkhead box protein O1 (FOXO1)/transforming growth factor-beta (TGF-β) axis. In non-serous ovarian cancer, overexpressed HDAC9 exerts antitumor effects that might be caused by the suppression of β-catenin signaling. Therefore, HDAC9 may be a potential target for individualized treatment of patients with different histological subtypes of ovarian cancer.

Cerebral ischemia-reperfusion injury is related to inflammation driven by free mitochondrial DNA. At the same time, the pro-inflammatory activation of macrophages, that is, polarization in the M1 direction, aggravates the cycle of inflammatory damage. They promote each other and eventually transform macrophages/microglia into neurotoxic macrophages by improving macrophage glycolysis, transforming arginine metabolism, and controlling fatty acid synthesis. Therefore, we propose targeting the mtDNA-driven inflammatory response while controlling the metabolic state of macrophages in brain tissue to reduce the possibility of cerebral ischemia-reperfusion injury.