Kidney diseases, mainly chronic kidney diseases and acute kidney injury, impose a heavy burden on global health care systems. However, traditional kidney-centric therapies, such as dialysis and renal transplantation, face limitations in terms of availability, efficiency and long-term sustainability. Kidney diseases are being increasingly recognized as systemic disorders orchestrated through dynamic interorgan communication. In addition to the kidney itself, multiple organs, such as the gut, liver, and heart, as well as the endocrine and nervous systems, interact to regulate renal function. This cross-talk involves metabolic signals, endocrine mediators, and neural pathways that collectively contribute to the modulation of kidney disease progression. The interactions among these pathways reveal novel therapeutic targets to alleviate kidney injury. However, causal links and organ-specific roles require further mechanistic investigation. This review highlights the need for a multisystem perspective in both the basic research and clinical management of kidney diseases, providing novel insights for the future development of effective, novel therapies targeting extrarenal organs to treat kidney diseases.

Understanding how biodiversity arises and how organisms adapt to different environments is fundamental to evolutionary biology. Hybridization may play an essential role in generating genetic diversity and promoting adaptation. In this work, we analyzed the population structure, demographic history, and selective landscapes of East Asian domestic pigs using a whole-genome resequencing dataset of 1,092 samples from 43 breeds. Our results indicate that North and South pigs form two deeply divergent lineages that split approximately 17,797 years ago, with no extant wild boar population identified as the direct ancestor of South pigs. In contrast, Central and Southwest pigs originated from a North ancestral background (∼9,012 years ago) with introgression from South pigs before their divergence (∼6,284 years ago), which was likely driven by bidirectional migrations between ancient northern and southern human populations in China. The North ancestry under selection contributed to increased body weight, while the South ancestry enhanced environmental adaptation through pathways involved in UV-B response, stress tolerance, and extracellular matrix remodeling. This South-derived ancestry facilitated the geographic expansion of North pigs into broader ecological zones, which led to the establishment of the Central and Southwest pigs. Specifically, we demonstrate that North-South hybridization increases genetic diversity and produces a mosaic inheritance pattern. Moreover, hybridization and adaptive introgression contribute to novel phenotypic variation in domesticated animals, offering valuable insights for genetic improvement and selective breeding.

Hypospadias is one of the most common birth defects in China and a key feature of differences in sex development (DSD), yet its genetic etiology remains largely unresolved. Current diagnostic approaches using DSD-targeted gene panels have a low rate of definitive diagnoses (5.5%), highlighting the need for more comprehensive genetic investigation. In this study, we performed next-generation sequencing (NGS) on the largest trio-based cohort of hypospadias to date, comprising 106 pediatric cases and their parents (92 trios). We achieved a definitive genetic diagnosis in 6.6% of patients, identifying pathogenic variants in canonical DSD genes such as AR, NR5A1 and WT1. By incorporating a broader spectrum of potentially clinically significant variants, we increased the overall genetic identification rate to 33.0% (35/106). Strikingly, trio analysis uncovered a significant burden of de novo loss-of-function (LoF) variants (2.2-fold enrichment, P=0.001), primarily driven by variants in genes associated with ciliopathies (10.35-fold, P=0.016), a previously underappreciated gene class in hypospadias. Furthermore, we identified and functionally validated two high-confidence risk genes, PRKCZ and HRNR, based on recurrent de novo variants. Functional assays confirmed that these variants disrupt key biological mechanisms, including cell proliferation, migration, and androgen signaling. Our large-scale trio approach substantially expands the genetic landscape of hypospadias, demonstrates the critical value of trio-based sequencing for improving diagnostic yield, and decisively implicates ciliary genes in its pathogenesis.

Biomolecular condensates formed through phase separation have emerged as a central principle of cellular organization, enabling the dynamic regulation of gene expression, signaling, metabolism, and stress responses. While early conceptual advances in condensate biology have largely originated from animal and in vitro systems, plant cells present a unique set of biological and technical challenges, including rigid cell walls, turgor pressure, plastid autofluorescence, complex endomembrane organization, and acute environmental responsiveness. These distinctive features impede the direct transfer of existing methodologies and drive the development of heterogeneous experimental practices. In this community comment, we present a comprehensive methodological framework for studying biomolecular condensates in plants, spanning in silico prediction, in vitro reconstitution, molecular dynamics simulations, live-cell and super-resolution imaging, material property measurements, membrane-associated condensates, and synthetic condensate engineering. We highlight best practices, common pitfalls, and plant-specific considerations, emphasizing the need for orthogonal validation, quantitative interpretation, and physiological relevance. By consolidating current methodologies and articulating shared principles, this review aims to establish a foundation for rigorous, reproducible, and conceptually coherent research in condensate biology of plants and beyond, with emerging implications for crop genetic improvement and synthetic biology applications.

Rapid climate change poses risks to vital ecosystem services, thereby threatening human societies that depend on these services. But how are ecosystem services prioritized by various stakeholders, and how might these differential priorities affect the evaluation of climate change impacts on ecosystem-service multifunctionality (ESMF)? To address these questions, we defined ESMF as the joint supply of multiple services relative to stakeholder demand, and conducted a social survey to obtain quantitative measures of ecosystem service prioritization from diverse stakeholders, such as pastoralists and biodiversity conservation agencies. Integrating these stakeholder-specific weightings with biophysical data from a decade-long climate change experiment, we found that stakeholders differed in their priorities, leading to differences in their evaluation of ESMF responses to climate change. Specifically, while warming and altered precipitation led to a decline in ESMF for groups prioritizing biodiversity conservation, multifunctionality was maintained or even increased for pastoralists, whose priorities focused almost entirely on forage provision. Similarly, warming was predicted to negatively impact the ESMF prioritized by environmental protection and biodiversity conservation agencies. These negative impacts were consistently stronger under dry climate conditions than under wet conditions. This work deepens our understanding of how stakeholder priorities shape the evaluation of climate change impacts on ESMF. This knowledge is essential for encouraging the development of appropriate and sustainable management strategies for local ecosystem services under climate change.

Engineered nanomaterials are frequently utilized as vectors for the targeted delivery of biomolecules such as DNA, RNA, proteins, and protein-nucleic acid complexes in mammalian cells, showing significant potential in medical applications. However, their use in plants remains limited. Little is known about the mechanisms of nanomaterial transport in plant cells and how their properties influence their internalization ability, which restricts their application in plant systems. In this review, we systematically summarize the translocation mechanism of nanomaterials within plant systems, and highlight how the size, shape, stiffness, and surface properties of nanomaterials affect their internalization in plants. Moreover, we discuss the types of cargoes and the transformation strategies employed in nanomaterial-mediated delivery. Finally, we highlight the key challenges and emerging opportunities associated with nanomaterial-based plant delivery systems, aiming to provide critical insights for advancing biomolecule delivery technologies in plant biotechnology.

Angiogenesis is critical for post-ischemic tissue repair. Although miR-485-5p is highly expressed in vascular tissues and RGS4 regulates angiogenesis, their specific roles under hypoxia remain largely unknown. This study aimed to elucidate these functions and underlying mechanisms. Using a CoCl2-induced hypoxic model in HUVECs, we observed that hypoxia significantly downregulated miR-485-5p expression while concurrently upregulating RGS4 mRNA levels. Notably, either inhibition of RGS4 or overexpression of miR-485-5p markedly enhanced HUVEC proliferation, migration, and tube formation. A luciferase reporter assay further confirmed that miR-485-5p directly targets RGS4. In addition, miR-485-5p overexpression or RGS4 inhibition increased the phosphorylation levels of VEGFR-2, AKT, and ERK1/2. Through co-immunoprecipitation assays, we revealed for the first time a direct interaction between RGS4 and VEGFR-2, which suppresses VEGF signaling and consequently impairs angiogenesis. Conversely, overexpression of RGS4 reversed the pro-angiogenic effects of miR-485-5p, as evidenced by reduced VEGFR-2/AKT/ERK1/2 phosphorylation and decreased proliferation, migration, and tube formation in HUVECs. These findings indicate that miR-485-5p promotes angiogenesis by downregulating RGS4. Consistent with these in vitro results, experiments in vivo using a rat hindlimb ischemia model confirmed that inhibition of RGS4 via si-RGS4 or overexpression of miR-485-5p via agomir-miR-485-5p markedly improved blood perfusion recovery, enhanced vascular angiogenesis, and increased VEGFR-2/AKT/ERK1/2 phosphorylation. Collectively, our study demonstrates that the miR-485-5p/RGS4 axis promotes hypoxia-induced angiogenesis by relieving RGS4-mediated inhibition of VEGFR-2/AKT/ERK1/2 signaling, thereby providing a strong rationale for targeting miR-485-5p as a possible treatment approach for lower extremity arterial disease.

Tumor-infiltrating CD8[+] T cells undergo aberrant lipid accumulation in the tumor microenvironment (TME), which triggers ferroptosis, drives T cell dysfunction, and impairs anti-tumor activity. However, strategies to protect the effector functions of CD8[+] T cells by preventing ferroptosis in vivo remain limited. Here, we report that menaquinone-4 (MK-4), a form of vitamin K2, serves as a potent ferroptosis inhibitor that preserves CD8[+] T cell function within the TME and enhances anti-tumor activity. Specifically, we demonstrated that MK-4 acts as a potent anti-ferroptotic agent in CD8[+] T cells, thereby restoring their effector cytotoxic potential. RNA sequencing (RNA-seq) analysis revealed that MK-4 reprograms the transcriptional landscape of CD8[+] T cells by reversing RSL3-induced ferroptosis-related gene expression, restoring effector-associated gene expression, and mitigating dysfunction and exhaustion programs. In adoptive cell transfer models, MK-4 pretreatment effectively suppressed ferroptosis in CD8[+] T cells, enhanced their effector functions, and inhibited tumor growth. Similarly, intravenous injection of MK-4 attenuated ferroptosis in endogenous CD8[+] T cells and strengthened their anti-tumor capacity. Furthermore, the combination of MK-4 with anti-programmed death-1 (PD-1) antibody therapy elicits a synergistic anti-tumor effect. Collectively, our findings reveal that MK-4 preserves CD8[+] T cell function by inhibiting ferroptosis, boosts anti-tumor immunity, thereby highlighting its potential as a therapeutic strategy for cancer treatment.

Adipose tissue protects metabolic homeostasis by storing excess fatty acids, releasing fuels during energy demand and coordinating endocrine and inflammatory signals. These functions are often described as linear pathways of lipogenesis, lipolysis, fatty acid oxidation and thermogenesis. However, lipid handling in adipocytes is spatially organized by organelle contact sites. The endoplasmic reticulum (ER), lipid droplets (LDs), mitochondria, peroxisomes and lysosomes form dynamic interfaces that determine whether fatty acids are stored safely, mobilized for oxidation, processed into specialized lipid species or redirected toward lipotoxic intermediates. In this review, we synthesize evidence that ER-LD and LD-mitochondria contacts coordinate lipid storage and oxidative use, whereas peroxisome-centred contacts connect lipolysis, very-long-chain and branched-chain fatty acid processing, plasmalogen metabolism and mitochondrial remodelling. We further discuss how autophagy and lysosomal pathways maintain adipocyte quality control by regulating LD turnover, mitophagy and membrane renewal. Finally, we propose that obesity, insulin resistance, ectopic lipid deposition, lipodystrophy and adipose inflammation can be viewed as different manifestations of impaired spatial lipid routing. This framework does not replace classical metabolic models, but provides a mechanistic layer that may help identify contact-site-dependent vulnerabilities in metabolic disease.