bims-ainimu 2026-03-22 papers

Issue of 2026–03–22
six papers selected by
Pedro Escoll Guerrero, Institut Pasteur

Chin Med J (Engl). 2026 Mar 17.

Ferroptosis-driven metabolic reprogramming in macrophages: Reshaping glucose utilization landscapes.

Yasheng Deng, Yafang Zheng, Qian Zhou, Taijin Lan, Qiu Chen.

ABSTRACT: Ferroptosis, an iron-dependent form of programmed cell death, has attracted significant attention in the field of immunometabolism. Macrophages, which are key immune cells, undergo metabolic reprogramming and polarization, influencing disease progression. This review investigates the interplay between ferroptosis signaling and macrophage glycometabolic reprogramming. To this end, it highlights the roles of iron, lipid, and amino acid metabolism in ferroptosis, alongside the distinct glycometabolic pathways in M1 and M2 macrophages. It also examines how gluconeogenesis, lactate, nicotinamide adenine dinucleotide phosphate, glycolysis, the tricarboxylic acid cycle, and the pentose phosphate pathway regulate ferroptosis. Furthermore, the review investigates the feedback mechanisms between macrophage polarization and ferroptosis signaling and discusses the implications of these interactions in diseases such as cancer, metabolic disorders, infections, neurodegenerative conditions, and cardiovascular diseases. Finally, it proposes therapeutic strategies targeting ferroptosis to modulate macrophage polarization, offering new insights for disease treatment. Thus, this work provides a foundation for understanding ferroptosis-macrophage metabolism interactions and identifies potential therapeutic targets.

Keywords: Ferroptosis; Glucose; Glycometabolic pathways; Macrophages; Metabolic reprogramming; Polarization

DOI: https://doi.org/10.1097/CM9.0000000000004046

Gut Microbes. 2026 Dec 31. 18(1): 2644681

Gut microbiota metabolic reprogramming drives the development of metabolic diseases in the host.

Yanrong Wang, Beibei Huang, Xue Wei, Yuanyuan Guan, Lingru Li, Yanfei Zheng, Wenlong Sun.

Metabolic diseases pose a major global health challenge, the pathogenesis of which centers on "metabolic reprogramming"; that is, the adaptive or pathological rewiring of metabolic pathways. Emerging evidence indicates that gut microbiota dysbiosis triggers its metabolic reprogramming prior to host disease onset and plays a pivotal role in the development of metabolic disorders. However, unlike host metabolic reprogramming, which has been well characterized, the pathogenic mechanisms resulting from gut microbiota metabolic reprogramming remain poorly understood, creating a critical knowledge gap regarding its role in systemic metabolic diseases. To address this gap, this review introduces the concept of gut microbiota metabolic reprogramming and establishes its foundational role in systemic metabolic disease. We propose that gut microbiota metabolic reprogramming constitutes an early pathogenic event, preceding and potentially driving subsequent metabolic alterations in the host. Within this framework, we systematically reveal that an imbalance in the gut microbiota leads to its significant metabolic reprogramming, including lipid, glucose, amino acid, and uric acid metabolism, which in turn regulates host-wide metabolic and immune homeostasis and contributes to the development of metabolic diseases. By integrating these mechanisms into a coherent model, our work provides a novel paradigm for understanding metabolic regulation. This model refines the fundamental pathophysiology of metabolic disorders and highlights new possibilities for targeting the microbiome for the prevention and treatment of metabolic disorders.

Keywords: Gut microbiota; metabolic diseases; metabolic reprogramming; metabolites

DOI: https://doi.org/10.1080/19490976.2026.2644681

J Clin Invest. 2026 Mar 16. pii: e197346. [Epub ahead of print]136(6):

Pathogen characteristics are key determinants of distinct host response phenotypes of sepsis.

Rishi Chanderraj, Brian Bartek, Kathleen A Stringer, Mohamad H Tiba, Michael W Sjoding, Ying He, Mark Nuppnau, Kale S Bongers, Mark D Adame, Sunny S Lou, V Eric Kerschberger, Matthew M Churpek, Carolyn S Calfee, Sandhya Tripathi, Debra M Foster, John A Kellum, Robert P Dickson, Pratik Sinha.

BACKGROUNDSepsis encompasses considerable biological and clinical heterogeneity. Previously, 2 phenotypes ("hyperinflammatory" and "hypoinflammatory") have been consistently identified within sepsis via latent class analysis. These phenotypes differ in their biological features, clinical outcomes, and therapeutic responses to interventions. Prior studies of sepsis heterogeneity have focused primarily on the host response. Here, we investigate the potential influence of the causative pathogen on sepsis heterogeneity and pathobiology.METHODSWe performed a retrospective observational analysis of 8,280 critically ill patients with sepsis to identify associations between pathogen characteristics and the hyperinflammatory and hypoinflammatory patient phenotypes. We also performed controlled murine and swine modeling of sepsis and lung injury and a secondary analysis of 449 patients enrolled in the EUPHRATES randomized controlled trial.RESULTSPathogen characteristics (pathogen identity, burden, virulence, and anatomic site of infection) were strongly and independently associated with the previously reported phenotypes. In a cohort of critically ill patients with sepsis, infection with gram-negative pathogens, primarily Enterobacterales spp. (e.g., Escherichia coli, Klebsiella pneumoniae), was strongly associated with the hyperinflammatory phenotype. The hyperinflammatory phenotype was also independently associated with increased pathogen burden, virulence, and initial anatomic site of infection. In controlled murine and swine modeling, both the identity and burden of the pathogen provoked key biological features of the hyperinflammatory phenotype. Among patients with sepsis, the prognostic value of lactate clearance varied substantially by phenotype. In a secondary analysis of a randomized trial of polymyxin B hemoadsorption (which removes circulating endotoxin), hypoinflammatory patients experienced worse survival.CONCLUSIONSOur results demonstrate the central importance of pathogen features in the clinical and biological heterogeneity of sepsis. Future studies of sepsis pathobiology and heterogeneity should expand their scope beyond the host response, as understanding pathogen-host interactions will be crucial in the development of precision therapeutic strategies to improve patient outcomes.TRIAL REGISTRATIONEUPHRATES trial NCT01046669.FUNDING5P30AG024824, IK2CX002766, R01HL144599, K24HL159247, R01HL158626, R01HL173531, R35GM142992, R35GM145330, R35GM136312, K23HL166880, R35HL140026.

Keywords: Bacterial infections; Immunology; Infectious disease; Microbiology

DOI: https://doi.org/10.1172/JCI197346

Front Immunol. 2026 ;17 1730799

Mechanisms and therapeutics of immunometabolic reprogramming driving macrophage-ECs interactions in sepsis-associated ARDS from the gut-lung axis perspective.

Jia Tang, Mi Yan, Yanfei Liu, Wanwei Li, Zhangxue Hu.

Acute respiratory distress (ARDS) caused by sepsis is a critical inflammatory condition with high mortality rates in clinical settings. The gut-lung axis plays a crucial role in regulating the immune response in both the intestinal and pulmonary environments, significantly impacting the development of ARDS. Immunometabolic reprogramming, a fundamental regulator of immune cell function, has recently been shown to profoundly affect the activity of macrophages and endothelial cells (ECs), as well as their crosstalk, thereby shaping the pathogenesis of ARDS. While a great deal has been learned about the potential inflammatory pathways involved, few clinically actionable therapies are available in part due to an incomplete understanding of gut-lung crosstalk in their shared ecosystem of cells and molecules. The current review systematically advances novel insights into the immunometabolic reprogramming that influences macrophage-ECs interactions via sepsis-induced ARDS, with a specific regard to the gut-lung axis. Here, we summarize the key biochemical pathways that control immune cell phenotypes and endothelial function, review the latest experimental evidence for their intercellular crosstalk, and describe the molecular targets that might be targeted to inform therapeutic strategies. Integrating the current evidence, this review seeks to provide a comprehensive theoretical framework and novel methods for the precise treatment of sepsis-associated ARDS, which could be beneficial to clinical practices and patients' prognoses.

Keywords: ARDS; ECS; cell interaction; gut-lung axis; immunometabolic reprogramming; inflammatory response; macrophages; sepsis

DOI: https://doi.org/10.3389/fimmu.2026.1730799

Front Immunol. 2026 ;17 1731805

Macrophage reprogramming and functional plasticity in sepsis.

Tengyue Huang, Huiling Cheng, Qianru Zhao, Min Li.

Sepsis remains one of the leading causes of mortality worldwide, driven not by the infection itself but by a dysregulated host response that spirals into a cytokine storm and subsequent immune paralysis. This maladaptive immune reaction frequently culminates in life-threatening complications, including multiple organ failure and acute lung injury. Among the immune cells orchestrating this process, macrophages serve as pivotal sentinels of the innate immune system, coordinating inflammatory and reparative programs in response to microbial and endogenous cues. Increasing evidence now reveals that their behavior during sepsis is profoundly shaped by epigenetic regulation. Dynamic changes in DNA methylation, histone modifications, and non-coding RNAs fine-tune macrophage activation, polarization, and memory throughout the septic course. This review will dissect how these epigenetic programs dictate the initiation, progression, and resolution of sepsis, integrating recent discoveries to clarify underlying mechanisms and highlight promising epigenetic targets for therapeutic intervention.

Keywords: epigenetics; immunity; macrophages; sepsis; therapy

DOI: https://doi.org/10.3389/fimmu.2026.1731805

Microbiol Spectr. 2026 Mar 18. e0287925

Metabolic activation of pyruvate cycle by protocatechualdehyde triggers oxidative killing of ampicillin-resistant Escherichia coli.

Liting Cheng, Yue Liu, Yifei Ge, Shuhan Yang, Tao Yuan, Sufang Kuang.

Antimicrobial resistance has emerged as a major global public health threat, underscoring the urgent need for novel therapeutic strategies. In this study, we demonstrate that protocatechualdehyde (PA), a natural compound derived from Salvia miltiorrhiza, exhibits potent and time-dependent bactericidal activity against ampicillin-resistant Escherichia coli. PA was also effective against AmpC β-lactamase-expressing strains and clinically isolated multidrug-resistant strains of E. coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, notably by exerting a combined effect with aminoglycoside antibiotics to overcome resistance. Mechanistically, integrated metabolomic and functional analyses reveal that PA induces a profound metabolic reprogramming in ampicillin-resistant Escherichia. coli, characterized by the hyperactivation of central carbon metabolism, with pyruvate catabolism serving as a critical hub. This forced metabolic flux leads to a surge in intracellular ATP and NADH, ultimately driving an overload of the electron transport chain and a lethal burst of reactive oxygen species (ROS). Genetic and chemical inhibition of the pyruvate dehydrogenase complex attenuates both ROS production and the bactericidal effect, confirming the causal link between metabolic disruption and bacterial death. PA treatment markedly improved survival and reduced bacterial burden in a murine systemic infection model, suggesting its therapeutic potential for infections. These findings provide a foundational rationale for developing PA-based therapeutics or derivatives to combat multidrug-resistant Gram-negative infections, particularly in combination with aminoglycoside antibiotics.IMPORTANCEThe rising prevalence of multidrug-resistant Gram-negative pathogens is limiting treatment options. This study identifies the natural compound PA as an effective bactericidal agent against ampicillin-resistant and clinically relevant multi-drug-resistant (MDR) Escherichia coli and other Gram-negative species. Importantly, we elucidate a previously unreported mechanism whereby PA hijacks bacterial central metabolism, specifically pyruvate metabolism, leading to metabolic overactivation, accumulation of NADH and ATP, and ultimately lethal reactive oxygen species (ROS) production. Furthermore, under the combined effect of PA and aminoglycoside antibiotics, their minimum inhibitory concentrations are reduced against resistant strains. These findings support the therapeutic potential of PA as either a standalone or adjunctive treatment for drug-resistant infections. This work emphasizes the value of targeting bacterial metabolism as a viable strategy to combat antimicrobial resistance.

Keywords: ampicillin-resistant Escherichia coli; metabolic regulation; natural compound; pyruvate metabolism

DOI: https://doi.org/10.1128/spectrum.02879-25