This study aims to investigate the expression of the SLC25 subfamily in sepsis-associated acute kidney injury (SA-AKI) and the role of SLC25A30 in regulating PINK1/PARKIN-mediated mitophagy. Transcriptome sequencing of renal tissues from lipopolysaccharide (LPS)-induced SA-AKI rats at multiple time points revealed time-dependent differential expression of SLC25 genes. At 12 h post-LPS injection (renal injury peak), 11 differentially expressed genes were identified. Intersection with Gene Expression Omnibus datasets and Gene Ontology enrichment highlighted 11 codifferentially expressed genes enriched in mitochondrial transmembrane transport. Notably, SLC25A30 was significantly negatively correlated with KIM-1 (r = -0.96) and LCN2 (r = -0.98). SLC25A30 was significantly downregulated in SA-AKI rat renal tissues and LPS-induced HK-2 cells, accompanied by upregulated PINK1/PARKIN, excessive mitophagy (elevated LC3B-II, decreased p62), and increased renal injury markers. SLC25A30 overexpression inhibited PINK1/PARKIN, reversed excessive mitophagy, reduced KIM-1 and LCN2 levels, alleviated mitochondrial dysfunction, enhanced cell viability, and exerted cytoprotective effects. PINK1 knockdown attenuated the regulatory effect of SLC25A30 on excessive mitophagy, indicating a dependence on the PINK1/PARKIN pathway. In conclusion, downregulated SLC25A30 is closely associated with excessive mitophagy in SA-AKI. SLC25A30 overexpression inhibits excessive mitophagy via downregulating the PINK1/PARKIN pathway, improves mitochondrial function, and alleviates HK-2 cell injury, suggesting that SLC25A30 may be a novel molecular target for SA-AKI-targeted therapy.

Isocitrate dehydrogenase (IDH)-mutant gliomas are primary malignant brain tumors defined by recurrent mutations in IDH1/2 genes and characterized by distinct molecular subtypes and relatively favorable clinical outcomes. Although these mutations represent early and defining events, recent data suggest that IDH1 mutant glial progenitor cells can reside within the histologically normal-appearing peritumoral cortex, indicating that cells harboring the founding driver mutation can persist beyond the tumor mass while retaining nonmalignant features. These observations challenge a purely gene-centric view of gliomagenesis. In this essay, we review emerging data supporting a multistep and context-dependent model in which the mutant IDH enzyme establishes an epigenetically altered cellular state, with subsequent genetic alterations and lineage-specific constraints that shape malignant progression. We further discuss the conceptual distinction between the "cell-of-mutation" and the "cell-of-origin" and consider how temporal stratification of tumor evolution may inform stage-specific therapeutic strategies along the transition from initiating clones beyond the tumor mass to overt tumors.

Bacteriophages (phages) are viruses that specifically infect bacteria and play a central role in shaping microbial communities and bacterial evolution. Beyond their protein-coding genes, phage genomes were found recently to encode small RNAs (sRNAs) that act post-transcriptionally to regulate host and viral gene expression. These phage-encoded sRNAs can influence infection dynamics, modulate host physiology, and determine the balance between lytic and lysogenic cycles. A prominent example is the phage lambda sRNA PreS, which enhances phage DNA replication by increasing translation of the host dnaN mRNA, linking host replication capacity to phage propagation. This review examines emerging evidence that phage-encoded sRNAs constitute a versatile and underappreciated class of molecular tools. We discuss how such RNAs could be repurposed as precision antibacterial agents in an era of increasing antibiotic resistance and outline key challenges and opportunities for developing RNA-based alternatives to conventional phage therapy.

The mitogen-activated protein kinase (MAPK) signaling pathway plays a key role in regulating a number of cellular processes, including proliferation, differentiation, apoptosis, and cellular responses to stress. In cancer, abnormal activation of some or all pathways of the MAPK cascade, particularly the RAS/RAF/MEK/ERK and p38/JNK signaling pathways, is common across many cancers as well as in an equal or disproportional measure in tumor initiation and progression. In the context of the tumor microenvironment (TME), the MAPK pathway facilitates complex interactions between cancer cells, stroma, and immune and endothelial cells. These interactions allow for elements of tumorigenesis, such as driving angiogenesis, immune suppression, and remodeling of the extracellular matrix, to all contribute to tumor survival and invasion. Additionally, MAPK signaling programs the response to cytokines and growth factor secretion by the TME beyond direct cellular responses, ultimately remodeling the TME in a favorable way for tumorigenesis. While targeting components of MAPK-related pathways has shown promise in the clinic, intrinsic and acquired resistance continues to develop in response to drug therapy composed of compensatory convoluted signaling, the activation of alternate signaling pathways, and TME-induced secondary feedback response. Recent data demonstrate that immune- and stroma-derived signals within the TME can sustain MAPK activity even under pharmacologic inhibition, providing the complexity of achieving durable therapeutic responses. As a result, it is crucial to gain consideration of the connections between MAPK signaling and the TME that may impart for sensitive strategies to elicit sustained drug-resistant treatment responses. Integrative therapies that incorporate MAPK inhibitors in conjunction with immunotherapy approaches, anti-angiogenic therapies, or metabolic modulators are also an important therapeutic strategy to elicit these adaptive pathways. This review will summarize our current understanding of the complex role of MAPK signaling in the TME, as well as propose broad ideas and potential future manipulation of MAPK-coordinated TME approaches for novel, durable cancer therapies.

Copper plays an essential role in numerous biological functions, requiring tight regulation to prevent toxicity and health complications. Cuproptosis is a recently discovered form of regulated cell death that occurs due to intracellular copper accumulation, with a unique mechanism distinct from other known cell death pathways. It is initiated when copper binds to lipoylated enzymes within the tricarboxylic acid (TCA) cycle, leading to enzyme aggregation, proteotoxic stress, and, ultimately, cell death. Since its identification, cuproptosis has drawn significant attention for its potential application in cancer therapy. Copper-based treatments have shown promise in suppressing tumor growth and may offer therapeutic strategies for tumors resistant to conventional chemotherapy. This article explores the underlying mechanisms of cuproptosis and the involvement of copper in various malignancies, aiming to advance targeted cancer therapies and inspire the development of novel anticancer agents that harness this pathway. Finally, important concepts of cuproptosis and issues to focus on in future studies are discussed.

Ferroptosis plays a crucial role in regulating tumor growth and represents a promising therapeutic target for nonsmall cell lung cancer (NSCLC). RNA-binding protein with serine-rich domain 1 (RNPS1) has been closely associated with the development of various cancer types, but its role in NSCLC remains unclear. In this study, we used lentiviral vectors to silence or overexpress RNPS1 in NSCLC cells and then assessed cell proliferation along with ferroptosis markers, such as lipid reactive oxygen species (ROS). Bioinformatics analysis revealed that RNPS1 was upregulated in clinical NSCLC samples. Consistently, functional experiments showed that overexpression of RNPS1 promoted cell proliferation, while RNPS1 knockdown inhibited cell proliferation. Furthermore, RNPS1 overexpression attenuated erastin-triggered ferroptosis by suppressing the accumulation of lipid ROS and malondialdehyde, as well as by preventing the depletion of glutathione. Mechanistic investigations identified that RNPS1 stabilized ETS variant transcription factor 4 (ETV4) mRNA. Importantly, blocking ETV4 expression partially reversed RNPS1 overexpression-mediated suppression of ferroptosis. Collectively, these results support the notion that RNPS1 acts as a novel suppressor of ferroptosis in NSCLC progression.

Dengue is the most important mosquito-borne viral infection of humans worldwide. Genetic ancestry of the host is a significant risk factor for severe dengue, but the mechanisms are not known. Recent findings using human skin explants from genetically defined donors reveal that dengue virus (DENV) replication and spread in skin increases with increasing proportion of European ancestry of the donor, associated with a strong inflammatory response and local myeloid cell infiltration, infection, and migration. In contrast, African ancestry is associated with substantially reduced cutaneous inflammation and cell infiltration following virus inoculation, resulting in reduced infection and migration of infected cells. These findings help explain the long-standing observation that individuals of African descent are relatively protected against severe dengue, while individuals of European descent are not. In this essay, we review DENV infection, focusing on human skin and the influence of genetic ancestry on the cutaneous innate response and virus spread.

Extracellular vesicles (EVs) have been investigated due to their natural biocompatibility and targeting capabilities. The specific approach of combining EVs with liposomes to create hybrid nanoparticles (ELNPs) for the delivery of the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas9) system for deletion of the HGF gene in stem cells, but their effectiveness in encapsulating large nucleic acids is limited due to their small size. This study aimed to knock out the HGF gene by the CRISPR/Cas9 system by ELNPs, and it was expected that the efficiency of the CRISPR/Cas9 system transfer would increase compared to the usual methods of using lipofectamine in stem cells from apical papilla (SCAPs). In this study, gRNA suitable for the HGF gene is designed first, and after insertion into the CRISPR/Cas9 vector, it enters Lipofectamine 2000. In the next step, ELNPs are prepared after collecting EVs and hybridizing them with liposomes containing CRISPR/Cas9 vector. Then, these integrated nanoparticles were presented to SCAPs, and the removal of HGF gene expression was evaluated at the level of RNA and protein. This study showed that the CRISPR/Cas9 system can be efficiently transferred to SCAP cells using ELNPs. Genomic DNA sequencing analyses of SCAP cells showed a unique pattern of mutation, highly likely mediated through EVs. Quantitative PCR and protein staining further showed a decrease in HGF gene expression in the knockout cells. Moreover, cell proliferation analysis showed a decrease in cell proliferation in KO-HGF adipose cells compared to the nonedited counterpart. In summary, this study highlights the supportive role of EVs in facilitating cell transfection and promoting a dominant DNA repair pattern, likely through an RNA-mediated mechanism, rather than the random insertions and deletions typically induced during CRISPR editing of the HGF gene in SCAPs.

Why plants need fertilization to produce seeds has long been discussed. We recently identified a new specialized tissue required for seed formation at the ovule's chalazal end, showing the final form of the phloem end and supporting its transport function; however, it is blocked by callose deposition. Callose is removed after central cell fertilization (open state), allowing nutrients to be transported to the seed. However, if fertilization fails, callose deposition persists (closed state), preventing the tissue from transporting nutrients. A β-1,3-glucanase gene, AtBG_ppap, was identified, and the AtBG_ppap mutant showed the closed state, producing smaller seeds due to incomplete callose degradation. Contrarily, the AtBG_ppap overexpression line produced larger seeds due to continuous callose degradation, showing that the tissue is the "gateway" for the seed nutrients.