Review
Abstract
Rheumatoid arthritis (RA) has a preclinical period of 5–10 years preceding the appearance of joint pain and swelling characteristic of clinical RA. Preclinical RA has been characterized by circulating IgA and IgG classes of autoantibodies targeting citrullinated protein antigens (ACPAs) that are highly specific for future clinical RA, circulating IgA plasmablasts, and autoantibody production at mucosal sites, all of which point toward mucosal tissues as the origin of immune dysregulation. In individuals at risk for developing and with established RA, oral and gut microbial shifts correlate with immune activation. Specific bacterial taxa such as Segatella copri, Subdoligranulum didolesgii, Eggerthella lenta, and Streptococcal species have been shown to contribute to the development and/or perpetuation of RA through mechanisms that include molecular mimicry, antigen citrullination, and disruption of mucosal immunity. Furthermore, microbial metabolites, including short-chain fatty acids, bile acids, and tryptophan derivatives, regulate immune homeostasis and offer potential therapeutic avenues. The gut microbiome also influences therapeutic responses by modulating conventional disease-modifying antirheumatic drugs. This Review synthesizes current knowledge on the bacterial microbiome’s role in RA pathogenesis and treatment responses, highlighting microbiome-targeted interventions as potential strategies for disease prevention and management.
Authors
Jing Li, Kristine A. Kuhn
Abstract
Metabolic dysfunction–associated steatohepatitis (MASH) is a progressive form of liver disease characterized by hepatocyte injury, inflammation, and fibrosis. The transition from metabolic dysfunction–associated steatotic liver disease (MASLD) to MASH is driven by the accumulation of toxic lipid and metabolic intermediates resulting from increased hepatic uptake of fatty acids, elevated de novo lipogenesis, and impaired mitochondrial oxidation. These changes promote hepatocyte stress and cell death, activate macrophages, and induce a fibrogenic phenotype in hepatic stellate cells (HSCs). Key metabolites, including saturated fatty acids, free cholesterol, ceramides, lactate, and succinate, act as paracrine signals that reinforce inflammatory and fibrotic responses across multiple liver cell types. Crosstalk between hepatocytes, macrophages, and HSCs, along with spatial shifts in mitochondrial activity, creates a feed-forward cycle of immune activation and tissue remodeling. Systemic inputs, such as insulin-resistant adipose tissue and impaired clearance of dietary lipids and branched-chain amino acids, further contribute to liver injury. Together, these pathways establish a metabolically driven network linking nutrient excess to chronic liver inflammation and fibrosis. This Review outlines how coordinated disruptions in lipid metabolism and intercellular signaling drive MASH pathogenesis and provides a framework for understanding disease progression across tissue and cellular compartments.
Authors
Gregory R. Steinberg, Andre C. Carpentier, Dongdong Wang
Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD), now the most common cause of chronic liver disease, is estimated to affect around 30% of the global population. In MASLD, chronic liver injury can result in scarring or fibrosis, with the degree of fibrosis being the best-known predictor of adverse clinical outcomes. Hence, there is huge interest in developing new therapies to inhibit or reverse fibrosis in MASLD. However, this has been challenging to achieve, as the biology of fibrosis and candidate antifibrotic therapeutic targets have remained poorly described in patient samples. In recent years, the advent of single-cell and spatial omics approaches that can be applied to human samples have started to transform our understanding of fibrosis biology in MASLD. In this Review, we describe these technological advances and discuss the new insights such studies have provided, focusing on the role of epithelial cell plasticity, mesenchymal cell activation, scar-associated macrophage accumulation, and inflammatory cell stimulation as regulators of liver fibrosis. We also consider how omics techniques can enhance our understanding of evolving concepts in the field, such as hot versus cold fibrosis and the mechanisms of liver fibrosis regression. Finally, we touch on future developments and how they are likely to inform a more mechanistic understanding about how fibrosis might differ between patients and how this could influence optimal therapeutic approaches.
Authors
Fabio Colella, Neil C. Henderson, Prakash Ramachandran
Abstract
Trained immunity (TRIM) is a form of long-lasting functional reprogramming of innate immune cells and their progenitors that enhances responsiveness to subsequent stimuli. Although first characterized in myeloid cells, TRIM was recently extended to nonmyeloid cell types, including endothelial and glial cells, which also exhibit stimulus-driven, memory-like behavior. While initially recognized as a protective mechanism, particularly in the context of vaccines and acute infections, TRIM can also become maladaptive, promoting chronic inflammation, immune dysfunction, and disease. This Review focuses on virus-induced TRIM while also addressing microbial, metabolic, and endogenous inducers. We examine key ligands and receptors that initiate TRIM and dissect the associated signaling and epigenetic pathways. Importantly, we argue that maladaptive TRIM arises not from a specific ligand, receptor, or molecular event, but from contextual factors such as stimulus persistence, dose, tissue microenvironment, and preexisting inflammation. The nature of the secondary challenge also shapes whether a trained response is adaptive or maladaptive. We further discuss TRIM induction in the bone marrow, involvement of both myeloid and nonmyeloid cells, and the role of lipid rafts in sustaining TRIM. We review maladaptive TRIM’s potential contribution to systemic diseases, such as atherosclerosis, diabetes, sepsis, cancer, and autoimmunity, along with its influence on viral vaccine responses. Finally, we outline potential strategies to redirect maladaptive TRIM and propose key outstanding questions for future research.
Authors
Dmitri Sviridov, Mihai G. Netea, Michael I. Bukrinsky
Abstract
Air pollution comprises a complex mixture of gaseous and particulate components. Particulate matter (PM) air pollution is associated with 4.7 million premature deaths per year. Among modifiable risk factors, air pollution exposure contributes to 8% of disability adjusted life years and ranks above factors such as high blood pressure, smoking, and high fasting plasma glucose. As the site of entry, exposure to PM air pollution causes respiratory symptoms and is a significant cause of respiratory morbidity and mortality. In this Review, we discuss the studies that link air pollution exposure with respiratory diseases. We review the epidemiological evidence linking PM exposure and lung diseases including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pneumonia, acute respiratory distress syndrome, and lung cancer. We also provide an overview of current knowledge about the mechanisms by which PM exerts its biological effects leading to adverse health effects in the respiratory system.
Authors
Robert B. Hamanaka, Gökhan M. Mutlu
Abstract
Inflammatory bowel diseases (IBDs) are complex immune disorders that arise at the intersection of genetic susceptibility, environmental exposures, and dysbiosis of the gut microbiota. Our understanding of the role of the microbiome in IBD has greatly expanded over the past few decades, although efforts to translate this knowledge into precision microbiome-based interventions for the prevention and management of disease have thus far met limited success. Here we survey and synthesize recent primary research in order to propose an updated conceptual framework for the role of the microbiome in IBD. We argue that accounting for gut microbiome context — elements such disease regionality, phase of disease, diet, medication use, and patient lifestyle — is essential for the development of a clear and mechanistic understanding of the microbiome’s contribution to pathogenesis or health. Armed with better mechanistic and contextual understanding, we will be better prepared to translate this knowledge into effective and precise strategies for microbiome restitution.
Authors
Megan S. Kennedy, Eugene B. Chang
Abstract
Pancreatic cancer has a 5-year survival rate of approximately 13% and is projected to become the second-leading cause of cancer-related deaths by 2040. Despite advances in preclinical research, clinical translation remains challenging, and combination chemotherapy remains the standard of care. The intrinsic heterogeneity of pancreas cancer underscores the potential of precision medicine approaches to improve patient outcomes. However, clinical implementation faces substantial challenges, including patient performance status, metastatic disease at diagnosis, intrinsic drug resistance, and a highly complex tumor microenvironment. Emerging targeted therapies, such as RAS inhibitors, offer promise for personalized treatment. These developments have prompted precision medicine–focused clinical trials using molecular subtyping for patient stratification. Effective development of precision medicine therapies depends heavily on robust preclinical models capable of accurately recapitulating the complexities of the pancreatic tumor microenvironment. Two-dimensional, air-liquid interface, and patient-derived organoid cultures combined with in vivo genetically engineered mouse models and patient-derived xenografts represent valuable experimental systems. This Review critically examines the strengths and limitations of these experimental model systems. We highlight their relevance and utility for advancing precision medicine strategies in pancreas cancer.
Authors
Vasiliki Pantazopoulou, Casie S. Kubota, Satoshi Ogawa, Kevin Christian Montecillo Gulay, Xiaoxue Lin, Hyemin Song, Jonathan R. Weitz, Hervé Tiriac, Andrew M. Lowy, Dannielle D. Engle
Abstract
The genetic landscape of pancreatic ductal adenocarcinoma (PDAC) is well-established and dominated by four key genetic driver mutations. Mutational activation of the KRAS oncogene is the initiating genetic event, followed by genetic loss of function of the CDKN2A, TP53, and SMAD4 tumor suppressor genes. Disappointingly, this information has not been leveraged to develop clinically effective targeted therapies for PDAC treatment, where current standards of care remain cocktails of conventional cytotoxic drugs. Nearly all (~95%) PDAC harbors KRAS mutations, and experimental studies have validated the essential role of KRAS mutation in PDAC tumorigenic and metastatic growth. Identified in 1982 as the first gene shown to be aberrantly activated in human cancer, KRAS has been the focus of intensive drug discovery efforts. Widely considered “undruggable,” KRAS has been the elephant in the room for PDAC treatment. This perception was shattered recently with the approval of two KRAS inhibitors for the treatment of KRASG12C-mutant lung and colorectal cancer, fueling hope that KRAS inhibitors will lead to a breakthrough in PDAC therapy. In this Review, we summarize the key role of aberrant KRAS signaling in the biology of pancreatic cancer; provide an overview of past, current, and emerging anti-KRAS treatment strategies; and discuss current challenges that limit the clinical efficacy of directly targeting KRAS for pancreatic cancer treatment.
Authors
Kristina Drizyte-Miller, Taiwo Talabi, Ashwin Somasundaram, Adrienne D. Cox, Channing J. Der
Abstract
The immune system must identify genuine threats and avoid reacting to harmless microbes because immune responses, while critical for organismal survival, can cause severe damage and use substantial energy resources. Models for immune response initiation have mostly focused on the direct sensing of microorganisms through pattern recognition receptors. Here, we summarize key features of the leading models of immune response initiation and identify issues they fail to solve individually, including how the immune system distinguishes between pathogens and commensals. We hypothesize and argue that surveillance of disruption to organismal homeostasis and core cellular activities is central to detecting and resolving relevant threats effectively, including infection. We propose that hosts use pattern recognition receptors to identify microorganisms and use sensing of homeostasis disruption to assess the level of threat they pose. We predict that both types of information can be integrated through molecular coincidence detectors (such as inflammasomes or others not yet discovered) and used to determine whether to initiate an immune response, its quality, and its magnitude. This conceptual framework may guide the identification of novel targets and therapeutic strategies to improve the progression and outcome of infection, cancer, autoimmunity, and chronic conditions in which inflammation plays a critical role.
Authors
Katharina Willmann, Luis F. Moita
Abstract
A central challenge in cancer therapy is the effective delivery of anticancer treatments while minimizing adverse effects on patient health. The potential dual impact of therapy is clearly illustrated in cancer-associated cachexia, a multifactorial syndrome characterized by involuntary weight loss, systemic inflammation, metabolic dysregulation, and behavioral alterations such as anorexia and apathy. While cachexia research often focuses on tumor-driven mechanisms, the literature indicates that cancer therapies themselves, particularly chemotherapies and targeted treatments, can initiate or exacerbate the biological pathways driving this syndrome. Here, we explore how therapeutic interventions intersect with the pathophysiology of cachexia, focusing on key organ systems including muscle, adipose tissue, liver, heart, and brain. We highlight examples such as therapy-induced upregulation of IL-6 and growth-differentiation factor 15, both contributing to reduced nutrient intake and a negative energy balance via brain-specific mechanisms. At the level of nutrient release and organ atrophy, chemotherapies also converge with cancer progression, for example, activating NF-κB in muscle and PKA/CREB signaling in adipose tissue. By examining how treatment timing and modality align with the natural trajectory of cancer cachexia, we underscore the importance of incorporating physiological endpoints alongside tumor-centric metrics in clinical trials. Such integrative approaches may better capture therapeutic efficacy while preserving patient well-being.
Authors
Tuba Mansoor Thakir, Alice R. Wang, Amanda R. Decker-Farrell, Miriam Ferrer, Rohini N. Guin, Sam Kleeman, Llewelyn Levett, Xiang Zhao, Tobias Janowitz
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