Shuang Liu

The global prevalence of metabolic diseases, notably obesity, diabetes mellitus, and thyroid disorders, has risen dramatically in recent decades, posing a significant threat to public health. While conventional pharmacological interventions remain the cornerstone of management, they face considerable limitations, including adverse effects and the development of drug resistance, underscoring the urgent need for alternative therapeutic strategies. Intriguingly, immune checkpoint molecules, originally recognized for their transformative role in cancer immunotherapy, are now gaining attention as pivotal regulators of metabolic homeostasis. Growing research demonstrates that immune checkpoint pathways, particularly the PD-1/PD-L1 axis, play dual roles in immune regulation and metabolic modulation by orchestrating inflammatory responses and energy metabolism. For instance, in obesity, PD-1/PD-L1 signaling promotes the polarization of adipose tissue macrophages from a proinflammatory M1 phenotype toward an anti-inflammatory M2 state, thereby mitigating chronic low-grade inflammation and associated metabolic dysfunction. These findings highlight the potential of immune checkpoint modulation as a novel therapeutic strategy for metabolic disorders. However, despite these advances, the role of immune checkpoints in metabolic diseases remains underexplored, with limited comprehensive reviews on the subject. This review comprehensively elucidates the pathophysiological mechanisms and translational potential of immune checkpoint regulation in obesity, diabetes, and thyroid disease while proposing novel directions for clinical intervention.

The aryl hydrocarbon receptor (AHR) is an environmental sensor in mammals and a ligand-dependent, highly conserved transcription factor. It belongs to the basic helix-loop-helix family of transcription factors and is the only known ligand-activated member within this family. Previous studies have revealed its significant roles in physiological regulation, metabolic homeostasis, and tumorigenesis. AHR governs transcriptional regulation and epigenetic modifications through diverse mechanisms and plays an important role in various types of cancer. In this review, we introduce the history and structure of AHR and summarize its modes of action via canonical and non-canonical pathways. We elaborate on the distinct impact of AHR on mitochondrial metabolism, epigenetics, as well as cell death and fate. Furthermore, we systematically discuss the relationship between AHR and tumor immunity. Finally, we explore the prospects of AHR in the tumor microenvironment, cancer immunity and therapy, and its potential as an immunotherapeutic target, along with current achievements in drug development targeting AHR. These research findings may provide insights into the relationship between AHR and its regulated molecules and pathways in cancer, as well as mechanisms for cancer treatment and intervention.

Obesity, a well-established risk factor for cancer development and progression, exerts its oncogenic effects primarily through metabolic reprogramming, particularly in lipid and amino acid metabolism. Despite its clinical significance, the molecular mechanisms linking obesity-induced metabolic alterations to lung adenocarcinoma progression remain elusive. In this study, we identify G protein-coupled receptor 162 (GPR162) as a pivotal metabolic-immune regulator in obesity-associated lung adenocarcinoma. Our findings reveal that GPR162 orchestrates tumor suppression through two distinct yet interconnected mechanisms: (1) GPR162 induces cell peroxidation by promoting the oxidation of medium-chain fatty acids such as decanoic acid and lauric acid. (2) GPR162 interacts with copper transporter SLC25A3 to form a functional complex in the mitochondria, driving copper influx and further promoting intracellular lipid peroxidation to induce cuproptosis, which directly kills tumor cells. The synergistic effect of fatty acid oxidation and cuproptosis not only reprogram the tumor metabolic microenvironment, but also induce the polarization of tumor-associated macrophages to M1 type, enhance CD8 ⁺ T cell infiltration and IFNγ secretion, and finally construct an immune microenvironment that inhibits tumor progression. This study provides a new target and theoretical basis for combined metabolic-immune treatment of obesity-related lung cancer.

Micronuclei are small, independent cytoplasmic structures containing nuclear material. They typically form during cell division due to DNA damage or division abnormalities, serve as biomarkers of genetic damage, and are closely associated with chromosomal instability (CIN). Emerging evidence suggests that micronuclei actively promote and exacerbate CIN, with significant implications in disease pathology and potential therapeutic applications. This review provides a comprehensive overview of micronuclei by exploring their origins, formation mechanisms, and functional consequences, and detailing the fate of micronuclei post-formation, which is essential for elucidating their role in genomic instability and potential therapeutic implications. Furthermore, micronuclei can contribute to extreme chromosomal shattering and genomic instability. These processes are increasingly recognized as critical contributors to disease progression, particularly in cancer. Although micronuclei have traditionally been viewed as markers of genomic instability, recent evidence suggests that they may also serve functional roles. Their potential use as treatments for certain diseases appears theoretically feasible; however, challenges remain in selectively targeting cells to induce the formation of favorable micronuclei and maintain optimal immune responses. Addressing these questions could open new avenues for therapeutic interventions.

The persistent high burden of lung cancer in China highlights a critical demand for the identification of new therapeutic targets and intervention approaches. Our initial integrative analysis of metabolomic and transcriptomic data revealed a previously uncharacterized tumor-suppressive mechanism mediated by CCDC6 in lung adenocarcinoma. We discovered an interaction between CCDC6 and ASS1, concomitant with marked reductions in citrulline and aspartate within tumor tissues. compared to the adjacent normal tissues. Additionally, co-stimulation with citrulline and aspartate induces ASS1 localization in the mitochondria ASS1 localized in the mitochondria, but the underlying mechanism remains unclear. This study aimed to delineate the dual tumor-suppressive actions of ASS1: firstly, through the recruitment of the deubiquitinase OTUD7A to remove ubiquitin chains from MFN1/2 and OPA1, thereby stabilizing the mitochondrial fusion machinery and inducing hyperfused network formation; and secondly, via the CCDC6-ASS1 complex, which instigates mitochondrial reactive oxygen species accumulation, compromises ATP synthesis, and reduces mitochondrial membrane potential, consequently inducing a state of metabolic dormancy in tumor cells. This study elucidates the mechanism by which the ASS1-CCDC6 axis suppresses lung adenocarcinoma progression by remodeling mitochondrial dynamics and metabolic homeostasis,, thereby establishing a theoretical basis for mitochondria-targeted precision therapy.