Mitophagy, an evolutionarily conserved quality-control process, selectively removes damaged mitochondria to maintain cellular homeostasis. Recent advances in our understanding of the molecular machinery underlying mitophagy — from receptors and stress-responsive triggers to lysosomal degradation — illustrate its key role in maintaining mitochondrial integrity and adapting mitochondrial function to ever-changing physiological demands. In this review, we outline the fundamental mechanisms of mitophagy and discuss how dysregulation of this pathway disrupts mitochondrial function and metabolic balance, driving a wide range of disorders, including neurodegenerative, cardiovascular, metabolic, and immune-related diseases, as well as cancer. We explore the dual role of mitophagy as both a disease driver and a therapeutic target, highlighting the efforts and challenges of translating mechanistic insights into precision therapies. Targeting mitophagy to restore mitochondrial homeostasis may be at the center of a large range of translational opportunities for improving human health.

Background Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with profound metabolic rewiring and resistance to therapy. Sodium-glucose co-transporter 2 (SGLT2) regulates glucose uptake, but its role in PDAC remains unclear. Methods SGLT2 expression was analyzed in clinical samples and public datasets. PDAC cell lines were subjected to genetic knockdown or canagliflozin (CANA) treatment to assess proliferation, migration, apoptosis, and glucose metabolism. Mechanistic studies investigated AMPK-ULK1 signaling, autophagy dynamics, oxidative stress, and EGFR signaling. Xenograft models were used to assess in vivo efficacy. Results SGLT2 was upregulated in PDAC and associated with poor prognosis. SGLT2 inhibition suppressed proliferation and migration while promoting apoptosis. Mechanistically, CANA induced ATP deficiency and initiated autophagy, but concurrently impaired autophagosome-lysosome fusion. This dual effect led to autophagic flux blockade, resulting in excessive ROS accumulation, mitochondrial dysfunction, and apoptosis. Inhibition of AMPK reduced ROS levels, while ROS scavenging partially rescued mitochondrial damage and cell death. Notably, SGLT2 inhibition enhanced sensitivity to EGFR-targeted therapy, producing synergistic anti-tumor effects in vitro and in vivo. Conclusions SGLT2 maintains metabolic and autophagic homeostasis in PDAC. Its inhibition induces metabolic stress, autophagic flux blockade, and ROS-driven mitochondrial apoptosis. In addition, targeting SGLT2 sensitizes tumors to EGFR-targeted therapy, offering a novel combinatorial strategy.

Nuclear protein 1 (NUPR1) is an intrinsically disordered, stress-adaptive regulator that sits at the intersection of transcriptional plasticity and proteostatic control, broadly upregulated across malignancies and tightly associated with poor prognosis. Here, we synthesize evidence positioning NUPR1 as a central node of tumor adaptation that integrates metabolic rewiring, proteostatic balance, and cell-death checkpoints into a unified stress-response framework. NUPR1 orchestrates lipogenic and glycolytic programs, sustains lysosomal biogenesis and autophagic flux, and governs cell-fate decisions by restraining apoptosis and ferroptosis through iron and redox control. Beyond tumor-intrinsic roles, NUPR1 remodels the tumor microenvironment by driving immunosuppressive macrophage polarization and amplifying inflammatory signaling, collectively sustaining a pro-survival niche. These circuits underpin broad therapeutic resistance across modalities, spanning chemotherapy, targeted agents, endocrine therapy, and immune checkpoint blockade. We further discuss the development of small-molecule NUPR1 antagonists—including ZZW-115 and emerging chemotypes—that disrupt nuclear trafficking and stress tolerance, alongside formulation strategies to optimize pharmacodynamic potency and safety. Together, these insights establish NUPR1 as a druggable stress-response node and provide a mechanistic framework to overcome resistance and refine adaptive cancer therapy paradigms.

Mitochondria are central to cellular homeostasis and play a critical role in aging and age-related disorders, making them promising therapeutical targets. Here, we identify terbinafine and miglustat as novel mitochondrial stress inducers that extend lifespan and improve healthspan in Caenorhabditis elegans. Through a two-step screening, we found that both compounds activate the mitochondrial stress response (MSR) and exhibit distinct mechanisms of action. Terbinafine and miglustat robustly activated the mitochondrial unfolded protein response (UPRmt) mediator ATFS-1, upregulated MSR pathways, and modulated mitochondrial function across species, similarly to doxycycline. Interestingly, both compounds also engaged the insulin/IGF-1 signaling (IIS) pathway in C. elegans, revealing an integrated stress response involving coordinated action of ATFS-1 and the FOXO transcription factor DAF-16, distinct from canonical IIS activation. Experiments in human HEK293T cells confirmed the translational potential, with both compounds inducing mitochondrial stress and modulating mitochondrial function in mammalian systems. This study highlights the potential of harnessing the MSR to promote longevity and mitigate age-related functional decline. The identification of terbinafine and miglustat as mitochondrial stressors paves the way for novel anti-aging therapies.

Painful diabetic peripheral neuropathy is recognized as a common and highly disabling complication in diabetes. Its underlying mechanisms remain incompletely understood, and effective therapeutic options are lacking. A growing body of evidence indicates that long noncoding RNAs, microRNAs, and messenger RNAs form complex competing endogenous RNA networks that influence painful diabetic peripheral neuropathy development. Given the central role of the dorsal root ganglion in sensory processing, this study investigated transcriptomic alterations in dorsal root ganglion tissue from a streptozotocin-induced rat model of painful diabetic peripheral neuropathy. Behavioral, electrophysiological, and histopathological assessments confirmed the successful establishment of neuropathic pain phenotypes. Whole-transcriptome RNA sequencing identified 101 messenger RNAs and 184 long non-coding RNAs that were differentially expressed. Key dysregulated genes included the proinflammatory cytokine Ccl3, the neurotrophic factor Igf1, the transcription factor Fosb, and the metabolic enzyme Alox15. Enrichment analyses indicated that these genes were mainly involved in immune-inflammatory responses, regulation of neurotransmission, ion channel activity, and energy metabolism. Construction of a competing endogenous RNA network showed that 1892 positively correlated long non-coding RNA-messenger RNA pairs contributed to a competing endogenous RNA network in which XR_005494971.1 was the most prominent long non-coding RNA regulator. Integration of microRNA predictions further identified rno-miR-466b-3p as a central node linking messenger RNAs and long non-coding RNAs. Reverse transcription-quantitative polymerase chain reaction and western blotting validated the sequencing results. These findings provide an integrated overview of coding and non-coding RNA interactions in a rat model of painful diabetic peripheral neuropathy and highlight molecular targets that may support early diagnosis and precision therapeutic strategies.

The sterile alpha and TIR motif containing 1 (SARM1) enzyme is a key driver of axonal degeneration in response to injury, making it an attractive target for treating chemotherapy-induced peripheral neuropathy (CIPN) and other nervous system diseases. In this study, we identified and optimised a class of base-exchange inhibitors (BEXi) targeting human SARM1 and explored their molecular interactions and conformational effects using cryo-EM, HDX-MS and SAXS. Although BEXi produced robust inhibition across all biochemical and cellular assay formats, application at sub-inhibitory concentrations consistently led to paradoxical SARM1 activation, and in neuronal assays, accelerated neurite degeneration. Further analysis showed that BEXi only delayed, rather than prevented, neurite degeneration when applied to primary neuronal cells, even at exceedingly high inhibitor concentrations. These results prompted us to discontinue BEXi development in favour of alternative strategies, underscoring the complexity of SARM1 as a therapeutic target and the need for comprehensive, mechanistically informed screening cascades.

Organoid biobanks represent a pivotal innovation at the intersection of stem cell biology, bioengineering, and precision medicine. By establishing standardized repositories of patient-derived organoids spanning diverse tissues and disease contexts, organoid biobanks enhance experimental reproducibility, foster international scientific collaboration, and accelerate translational research. This study presents a comprehensive bibliometric analysis of 1,318 publications over the past three decades and identifies transformative shifts in the field. Research output has increased substantially since 2014, driven by international consortia involving institutions in China, the United States, and Europe. The analysis highlights predominant applications in cancer modeling (particularly gastrointestinal and central nervous system malignancies), high-throughput drug screening, and regenerative medicine, with emerging frontiers in multi-organ system integration and artificial intelligence-enabled predictive modeling. Technological advances are increasingly being evaluated for clinical relevance through reported concordance between organoid-based predictions and patient treatment responses. While challenges persist in the functional maturation of organoids and in ethical governance, organoid biobanks are increasingly positioned to reshape biomedical research paradigms by bridging experimental models with clinical decision-making. The strategic development of standardized protocols and interdisciplinary frameworks will be essential to realize their full potential in advancing therapeutic discovery and personalized healthcare.

Cholangiocarcinoma (CCA) is an aggressive malignancy characterized by limited therapeutic options and poor prognosis, largely attributed to the presence of cancer stem cells (CSCs). These CSCs serve as pivotal drivers of tumor heterogeneity, chemotherapy resistance, and disease recurrence. CSCs in CCA exhibit remarkable plasticity, a characteristic sustained through metabolic state alterations and intricate interactions with the tumor microenvironment (TME), which collectively enhance their self-renewal and survival potential. While advancements have been made in understanding metabolic reprogramming of CCA CSCs, translating these findings into clinical applications encounters significant challenges, including insufficient target specificity, complex metabolic heterogeneity, and the profound complexity of the TME. This review provides a systematic evaluation of metabolic reprogramming mechanisms in CCA CSCs, with critical analysis of stemness-maintaining signaling pathways, oxidative phosphorylation (OXPHOS), nutrient utilization, metabolic crosstalk within the TME, autophagy regulation, and ferroptosis resistance. We emphasize emerging strategies to therapeutically target the interconnected metabolic networks essential for CSC functionality and survival, with the goal of establishing a theoretical basis for innovative precision therapies to enhance clinical outcomes for CCA patients.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and resistance to systemic therapies remains a significant clinical challenge. This study investigated the mechanisms by which metabolic reprogramming contributes to systemic treatment resistance in HCC. We established HCC cell lines with multidrug resistance characteristics and observed enhanced metabolic activity in these cells. Integrated multiomics analyses revealed hyperactive glucose‒lipid and glutathione metabolic pathways that play critical roles in supporting tumor cell proliferation and survival. We constructed a metabolic reprogramming atlas for HCC-resistant cells and identified aldo-keto reductase (Aldo-keto reductase family 1 Member B1, AKR1B1) as a key regulator of this reprogramming, which sustains drug resistance by regulating energy metabolism and enhancing stress tolerance. Importantly, AKR1B1 expression levels are closely associated with drug resistance and poor prognosis in HCC patients. The secretory nature of AKR1B1 not only underscores its predictive value but also facilitates the intercellular transmission of drug resistance. In terms of overcoming resistance, the AKR1B1 inhibitor epalrestat significantly mitigated drug resistance when it was used in combination with standard therapies. These findings underscore the importance of metabolic reprogramming in the development of HCC resistance. AKR1B1, a key enzyme that regulates metabolic reprogramming, has been identified as a potential biomarker and therapeutic target, providing new insights into overcoming resistance in HCC treatment.

The gut microbiome is crucial in regulating overall physiology and communicates with the host through various microbial-derived metabolites, including secondary bile acids (BAs). However, mechanisms underlying the gut microbiome-BA crosstalk (gMxB) are still poorly understood. Here, we assess the postprandial cecal microbiome, BA levels, and colon transcriptome of male BXD mice fed with a chow or high-fat diet, and find that genetic and dietary factors shift microbiome composition and affect gMxB. Four diet-dependent co-mapping genetic loci associated with gMxB, including the interaction between Turicibacter sanguinis - plasma cholic acid, are identified using systems genetics approaches. By integrating human MiBioGen database, we prioritize PTGR1 and PTPRD as candidate genes potentially regulating identified gMxB. The human relevance of these candidates on metabolic health is investigated using data from the UK biobank, FinnGen, and million veteran program databases. Overall, this study illustrates potential modulators regulating gMxB and provides insights into gut microbiome-host communication.

Immunotherapy for cardiovascular diseases (CVDs) holds great promise for precision management by modulating localized immune-inflammatory responses. The interplay between focal cardiovascular pathology and panvascular disease, necessitates highly integrated therapeutic strategies. Nano-technology-based theranostic platforms address this challenge by enabling both regulation and real-time imaging of immune cell activity within cardiovascular lesions. These functional nanotherapy systems not only halt disease progression at pathological sites but also reduce secondary cardiovascular events driven by shared inflammatory mechanisms. Additionally, nanoplatform-based dynamic visualization of immune cell responses facilitates adaptive, personalized interventions. This review introduces the role of immune cells in CVDs. It summarizes recent advances in nanomaterial-based immunomodulation strategies, including mechanisms of immune regulation, enhanced imaging, and therapeutic applications in atherosclerosis, myocardial infarction, ischemic stroke, abdominal aortic aneurysm, and myocarditis. Collectively, this integrated nanotheranostic paradigm establishes a robust foundation for the next generation of cardiovascular precision medicine.

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Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H+-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive transcriptional response typified by induction of a set of transcripts involved in lysosomal function and proteolysis, which we termed the lysosomal surveillance response (LySR). LySR activation is characterized by boosted lysosomal activity and enhanced clearance of protein aggregates in worm models of Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis, thereby improving fitness. The GATA transcription factor ELT-2 governs the LySR programme and its associated beneficial effects. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan.

Background:. Pancreatic ductal adenocarcinoma (PDAC) poses a serious threat to human health with high mortality and poor prognosis, and there is an urgent need to explore the pathogenesis of PDAC in order to search for new therapeutic targets. Methods:. The expression of laminin γ-2 (LAMC2) in PDAC and its effect on the prognosis of tumor patients were predicted by an online database, and the expression level of LAMC2 in pancreatic cancer was verified by polymerase chain reaction (PCR) and western blot; flow cytometry, wound healing assay, Cell counting kit-8 (CCK8) assay, and colony formation assay were used to explore the effect of LAMC2 on the proliferation and migration of pancreatic cancer cells; and we also probed the potential relationship between LAMC2 and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling. Results:. High levels of LAMC2 in pancreatic cancer may benefit tumor proliferation migration and invasion and lead to poor prognosis of tumor patients. The mechanism by which LAMC2 promotes PDAC progression may be related to the activation of PI3K/Akt signaling to influence apoptosis and cell cycle. Conclusions:. LAMC2 promotes proliferation migration invasion of PDAC and leads to poor prognosis in pancreatic cancer patients.

The gut microbiome is crucial in regulating overall physiology and communicates with the host through various microbial-derived metabolites, including secondary bile acids (BAs). However, mechanisms underlying the gut microbiome-BA crosstalk (gMxB) are still poorly understood. Here, we assessed the postprandial cecal microbiome, BA levels, and colon transcriptome of a genetically diverse population of 32 BXD mouse strains fed with a chow or high-fat diet, and found that genetic and dietary factors shift microbiome composition and gMxBs. Four diet-dependent co-mapping genetic loci associated with gMxBs, such as the interaction between Turicibacter-plasma cholic acid, were identified using systems genetics approaches. By integrating human MiBioGen database, we prioritized PTGR1, PTPRD, and GABRB3 as candidate genes potentially regulating gMxBs. The human relevance of these candidates on metabolic health was demonstrated using the UK biobank, FinnGen, and million veteran program. Overall, this study illustrates potential modulators regulating gMxBs and provides insights into gut microbiome-host communication.

The incidence and mortality of digestive system-related cancers have always been high and attributed to the heterogeneity and complexity of the immune microenvironment of the digestive system. Furthermore, several studies have shown that chronic inflammation in the digestive system is responsible for cancer incidence; therefore, controlling inflammation is a potential strategy to stop the development of cancer. Innate Lymphoid Cells (ILC) represent a heterogeneous group of lymphocytes that exist in contrast to T cells. They function by interacting with cytokines and immune cells in an antigen-independent manner. In the digestive system cancer, from the inflammatory phase to the development, migration, and metastasis of tumors, ILC have been found to interact with the immune microenvironment and either control or promote these processes. The conventional treatments for digestive tumors have limited efficacy, therefore, ILC-associated immunotherapies are promising strategies. This study reviews the characterization of different ILC subpopulations, how they interact with and influence the immune microenvironment as well as chronic inflammation, and their promotional or inhibitory role in four common digestive system tumors, including pancreatic, colorectal, gastric, and hepatocellular cancers. In particular, the review emphasizes the role of ILC in associating chronic inflammation with cancer and the potential for enhanced immunotherapy with cytokine therapy and adoptive immune cell therapy.

ObjectiveTo quantitatively study the measurement data related to the bony posterior cranial fossa and explore the correlation between bony posterior cranial fossa morphology and the occurrence of hemifacial spasm.MethodsA total of 50 patients with hemifacial spasm who attended the Department of Neurosurgery of China-Japan Friendship Hospital from October 2021 to February 2022 were included, and 60 patients with minor head trauma excluding skull fracture and intracranial abnormalities were included as controls. Cranial multilayer spiral CTs (MSCTs) were performed in both groups, and multiplanar reconstruction (MPR) was used as a postprocessing method to measure data related to the posterior cranial fossa in both groups.ResultsCompared with the control group, the anteroposterior diameter (labeled AB) and the height (labeled BE) of the bony posterior cranial fossa, the anteroposterior diameter of the foramen magnum (labeled BC), the length of the clivus (labeled AB), and the length of the posterior occipital (labeled CD) in the HFS group were all reduced, and the differences were statistically significant. BE is positively correlated with AB and CD, with a stronger correlation observed between BE and AB (r = 0.487, p < 0.01). AB is negatively correlated with AD (r = −0.473, p < 0.01). The remaining correlations between the data were not statistically significant. There was no overlap in the 95% confidence interval for any of the measurements between the hemifacial spasm group and the control group.ConclusionThere is a correlation between the posterior cranial fossa and hemifacial spasm.