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The procurement and management of nutrients and ability to fight infections are fundamental requirements for survival. These defense responses are bioenergetically costly, requiring the immune system to balance protection against pathogens with the need to maintain metabolic homeostasis. NF-κB transcription factors are central regulators of immunity and inflammation. Over the last two decades, these factors have emerged as a pivotal node coordinating the immune and metabolic systems in physiology and the etiopathogenesis of major threats to human health, including cancer, autoimmunity, chronic inflammation, and others. In this review, we discuss recent advances in understanding how NF-κB-dependent metabolic programs control inflammation, metabolism, and immunity and how improved knowledge of them may lead to better diagnostics and therapeutics for widespread human diseases. NF-κB is central to immune and inflammatory responses but a long-standing question is if and how NF-κB integrates host responses against injury and microbial pathogens by reprogramming cell metabolism. A recent flurry of studies has now partially resolved this conundrum, underscoring how the NF-κB transcriptional machinery is inherently hardwired to the metabolic programs that govern immune regulation, energy homeostasis, and oncogenesis. The NF-κB subunit Rel is a major regulator of energy metabolism and biosynthetic pathways in germinal center B cells and human B cell lymphomas, and treatment with small-molecules REL inhibitors can effectively counteract lymphomagenesis in certain preclinical animal models. NF-κB-regulated metabolic enzymes such as 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase isoform (3PFKFB3), glutamate dehydrogenase 1 (GDH1), and carboxylesterase 1 (CES1), are pivotal effectors of NF-κB-dependent metabolic adaptation of cancer cells to nutrient deprivation and, as such, represent potentially actionable therapeutic targets in oncology. Rel/REL mediates an innate immune checkpoint that governs the generation, function, and metabolism of myeloid-derived suppressor cells (MDSCs) and can promote oncogenesis by suppressing antitumor immune responses. REL inhibition might enhance the therapeutic efficacy of current immune checkpoint immunotherapies. The activation of NF-κB in cancer-associated fibroblasts in response to tumor-secreted lactate can promote therapy resistance in lung cancer cells by increasing the secretion of hepatocyte growth factor (HGF). NF-κB is a major sensor of metabolic imbalances that result in inflammasome activation. Understanding how NF-κB-dependent metabolic regulation governs physiology and disease states opens new opportunities for therapeutic intervention in cancer and immune-mediated diseases. [ABSTRACT FROM AUTHOR]

Constitutive NF-κB signalling has been implicated in the pathogenesis of most human malignancies and virtually all non-malignant pathologies. Accordingly, the NF-κB pathway has been aggressively pursued as an attractive therapeutic target for drug discovery. However, the severe on-target toxicities associated with systemic NF-κB inhibition have thus far precluded the development of a clinically useful, NF-κB-targeting medicine as a way to treat patients with either oncological or non-oncological diseases. This minireview discusses some of the more promising approaches currently being developed to circumvent the preclusive safety liabilities of global NF-κB blockade by selectively targeting pathogenic NF-κB signalling in cancer, while preserving the multiple physiological functions of NF-κB in host defence responses and tissue homeostasis. [ABSTRACT FROM AUTHOR]

Summary Constitutive NF-κB signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-κB-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-κB-regulated antiapoptotic factor GADD45β and the JNK kinase MKK7 as a therapeutic target in MM. Using a drug-discovery strategy, we developed DTP3, a D-tripeptide, which disrupts the GADD45β/MKK7 complex, kills MM cells effectively, and, importantly, lacks toxicity to normal cells. DTP3 has similar anticancer potency to the clinical standard, bortezomib, but more than 100-fold higher cancer cell specificity in vitro. Notably, DTP3 ablates myeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-κB pathway is possible and, at least for myeloma patients, promises a profound benefit. [ABSTRACT FROM AUTHOR]