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Energy reallocation is critical for organismal survival under developmental transitions and nutrient restriction. However, whether developmentally and nutritionally induced energy deficiency are governed by convergent regulatory mechanisms remains poorly understood. Here, we identify miR‐375‐3p as a central regulator that coordinates energy use during both pupal metamorphosis and starvation using the Tribolium castaneum . Upregulated by endocrine cues including 20‐hydroxyecdysone and insulin, miR‐375‐3p redirects energy by suppressing de novo lipogenesis through fatty acid synthase ( FASN ) and enhancing lipolysis via Relish inhibition. This regulatory shift mobilizes stored reserves while suppressing energetically costly immune and oxidative responses, thereby prioritizing energy supply to the central nervous system. Under fed conditions, miR‐375‐3p levels decline, restoring energy distribution across all tissues and enabling immune competence. These findings reveal a conserved miRNA‐centered mechanism that mediates metabolic adaptation to energy scarcity and provide new insights into miRNA‐driven control of energy balance.

Sepsis is a complex condition marked by significant dysregulation of immune and metabolic processes, leading to multi-organ failure. Macrophages, key mediators of immune activity, demonstrate functional flexibility by switching between pro- and anti-inflammatory phenotypes in response to inflammatory and metabolic signals in their local environment. During sepsis, pathogen-derived signals activate host defense responses that impair intercellular oxygen transport, increase oxygen consumption by immune cells within inflamed tissues, and promote a metabolic transition toward aerobic glycolysis. This metabolic transition supports immune defense mechanisms, and the metabolic by-products further regulate immune activation through feedback in key signaling cascades, promoting a transition toward tolerance during the resolution phase. Since mitochondria are central hubs for cellular energy homeostasis, they play a crucial role in this process. Mitochondrial dysfunction and metabolic changes are now recognized as major contributors to the progression of sepsis. The accumulation of mitochondria-derived metabolites can further modulate immune signaling pathways, actively influencing macrophage function. Therefore, this review emphasizes the crosstalk between macrophage polarization and mitochondrial changes, with a focus on new molecular insights and the potential of mitochondrial pathways as biomarkers or therapeutic targets. These concepts provide a foundation for advancing both experimental research and clinical applications, potentially guiding future interventions to better manage sepsis and its associated mortalities.

In the lungs, macrophages constitute the first line of defense against pathogens and foreign bodies and play a fundamental role in maintaining tissue homeostasis. Activated macrophages show altered immunometabolism and metabolic changes governing immune effector mechanisms, such as cytokine secretion characterizing their classic (M1) or alternative (M2) activation. Lipopolysaccharide (LPS)-stimulated macrophages demonstrate enhanced glycolysis, blocked succinate dehydrogenase (SDH), and increased secretion of interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). Glycolysis suppression using 2 deoxyglucose in LPS-stimulated macrophages inhibits IL-1β secretion, but not TNF-α, indicating metabolic pathway specificity that determines cytokine production. In contrast to LPS, the nature of the immunometabolic responses induced by non-organic particles, such as silica, in macrophages, its contribution to cytokine specification, and disease pathogenesis are not well understood. Silica-stimulated macrophages activate pattern recognition receptors (PRRs) and NLRP3 inflammasome and release IL-1β, TNF-α, and interferons, which are the key mediators of silicosis pathogenesis. In contrast to bacteria, silica particles cannot be degraded, and the persistent macrophage activation results in an increased NADPH oxidase (Phox) activation and mitochondrial reactive oxygen species (ROS) production, ultimately leading to macrophage death and release of silica particles that perpetuate inflammation. In this manuscript, we reviewed the effects of silica on macrophage mitochondrial respiration and central carbon metabolism determining cytokine specification responsible for the sustained inflammatory responses in the lungs.

Glutathione is an essential metabolite for plant life best known for its role in the control of reactive oxygen species (ROS). Glutathione is also involved in the detoxification of methylglyoxal (MG) which, much like ROS, is produced at low levels by aerobic metabolism under normal conditions. While several physiological processes depend on ROS and MG, a variety of stresses can dramatically increase their concentration leading to potentially deleterious effects. In this review, we examine the structure and the stress regulation of the pathways involved in glutathione synthesis and degradation. We provide a synthesis of the current knowledge on the glutathione-dependent glyoxalase pathway responsible for MG detoxification. We present recent developments on the organization of the glyoxalase pathway in which alternative splicing generate a number of isoforms targeted to various subcellular compartments. Stress regulation of enzymes involved in MG detoxification occurs at multiple levels. A growing number of studies show that oxidative stress promotes the covalent modification of proteins by glutathione. This post-translational modification is called S-glutathionylation. It affects the function of several target proteins and is relevant to stress adaptation. We address this regulatory function in an analysis of the enzymes and pathways targeted by S-glutathionylation.

Neutrophils are the most abundant, short lived, and terminally differentiated leukocytes with distinct tiers of arsenals to counter pathogens. Neutrophils were traditionally considered transcriptionally inactive cells, but recent researches in the field led to a paradigm shift in neutrophil biology and revealed subpopulation heterogeneity, and functions pivotal to immunity and inflammation. Furthermore, recent unfolding of metabolic plasticity in neutrophils has challenged the long-standing concept of their sole dependence on glycolytic pathway. Metabolic adaptations and distinct regulations have been identified which are critical for neutrophil differentiation and functions. The metabolic reprogramming of neutrophils by inflammatory mediators or during pathologies such as sepsis, diabetes, glucose-6-phosphate dehydrogenase deficiency, glycogen storage diseases (GSDs), systemic lupus erythematosus (SLE), rheumatoid arthritis, and cancer are now being explored. In this review, we discuss recent developments in understanding of the metabolic regulation, that may provide clues for better management and newer therapeutic opportunities for neutrophil centric immuno-deficiencies and inflammatory disorders.

The metabolic abnormality observed in tumors is characterized by the dependence of cancer cells on glycolysis for their energy requirements. Cancer cells also exhibit a high level of reactive oxygen species (ROS), largely due to the alteration of cellular bioenergetics. A highly coordinated interplay between tumor energetics and ROS generates a powerful phenotype that provides the tumor cells with proliferative, antiapoptotic, and overall aggressive characteristics. In this review article, we summarize the literature on how ROS impacts energy metabolism by regulating key metabolic enzymes and how metabolic pathways e.g., glycolysis, PPP, and the TCA cycle reciprocally affect the generation and maintenance of ROS homeostasis. Lastly, we discuss how metabolic adaptation in cancer influences the tumor’s response to chemotherapeutic drugs. Though attempts of targeting tumor energetics have shown promising preclinical outcomes, the clinical benefits are yet to be fully achieved. A better understanding of the interaction between metabolic abnormalities and involvement of ROS under the chemo-induced stress will help develop new strategies and personalized approaches to improve the therapeutic efficiency in cancer patients.

Thermophiles and psychrophiles, adapted to extreme temperatures, thrive in hot and cold environments, respectively. Despite their importance to biotechnology and environmental research, their adaptation mechanisms remain unclear. We have performed a comparative analysis of the genomes and metabolic networks of these species. Psychrophiles were found to have larger genomes, more genes, bigger metabolic networks, fewer metabolite exchanges, and higher growth rates compared to thermophiles. These species show amino acid and codon preferences: thermophiles favor GC-rich codons, while psychrophiles prefer AT-rich ones. This aligns with their genomic G + C content, which is higher in thermophiles and linked to their growth. Compared to mesophiles, species which are living in normal conditions, extremophiles show significantly reduced metabolite exchange, with psychrophiles importing fewer nutrients and thermophiles exporting fewer metabolites. Both groups exhibit distinct active metabolic reactions enriched with unique and important processes. In summary, both thermophiles and psychrophiles exhibit unique genomic profiles and metabolic network properties that likely support their adaptation to extreme temperatures.

As a common endocrinopathy of reproductive-aged women, polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. It is linked with insulin resistance through preferential abdominal fat accumulation that is worsened by obesity. Over the past two millennia, menstrual irregularity, male-type habitus and sub-infertility have been described in women and confirm that these clinical features of PCOS were common in antiquity. Recent findings in normal-weight hyperandrogenic PCOS women show that exaggerated lipid accumulation by subcutaneous (SC) abdominal stem cells during development to adipocytes in vitro occurs in combination with reduced insulin sensitivity and preferential accumulation of highly-lipolytic intra-abdominal fat in vivo. This PCOS phenotype may be an evolutionary metabolic adaptation to balance energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction. This review integrates fundamental endocrine-metabolic changes in healthy, normal-weight PCOS women with similar PCOS-like traits present in animal models in which tissue differentiation is completed during fetal life as in humans to support the evolutionary concept that PCOS has common ancestral and developmental origins.

For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role. Highlights 1. Attempting to delineate the complex and multidimensional interplays between metabolites (or metabolic enzymes) and predominant immune cell populations. 2. Metabolic checkpoints of immune cells are described and the contribution of these metabolic targets to determine the metabolic adaptations of distinct immune cells in specific tissue environments is emphasized. 3. Proposed cancer-immunometabolism subcycle, enriching the theoretical foundation of the cancer-immunology field. 4. Metabolism-induced disturbances in the acid-base balance of the tumor microenvironment have non-redundant effects on immunotherapy. 5. Pending challenges and clinical concerns in metabolic insights were addressed.

Cellular metabolism is a crucial determinant of immune cell fate and function. Extensive studies have demonstrated that metabolic decisions influence immune cell activation, differentiation, and cellular capacity, in the process impacting an organism’s ability to stave off infection or recover from injury. Conversely, metabolic dysregulation can contribute to the severity of multiple disease conditions including autoimmunity, alloimmunity, and cancer. Emerging data also demonstrate that metabolic cues and profiles can influence the success or failure of adoptive cellular therapies. Importantly, immunometabolism is not one size fits all; and different immune cell types, and even subdivisions within distinct cell populations utilize different metabolic pathways to optimize function. Metabolic preference can also change depending on the microenvironment in which cells are activated. For this reason, understanding the metabolic requirements of different subsets of immune cells is critical to therapeutically modulating different disease states or maximizing cellular function for downstream applications. Fatty acid oxidation (FAO), in particular, plays multiple roles in immune cells, providing both pro- and anti-inflammatory effects. Herein, we review the major metabolic pathways available to immune cells, then focus more closely on the role of FAO in different immune cell subsets. Understanding how and why FAO is utilized by different immune cells will allow for the design of optimal therapeutic interventions targeting this pathway.