The persistence of castration-resistant prostate cancer (CRPC) despite androgen deprivation therapy and androgen receptor (AR) signaling inhibition underscores the need to elucidate resistance mechanisms. The AR signaling pathway plays a central role in the development of prostate cancer. Metabolic reprogramming of androgen synthesis and aberrant activation of AR signaling collectively drive CRPC development. Under therapeutic pressure, AR signaling adapts through AR amplification, ligand-binding domain mutations, splice variants, and alternative activation by cytokines/growth factors, maintaining AR transcriptional activity in low-androgen environments. Concurrently, somatic alterations (like PTEN loss) and crosstalk with key pathways such as PI3K/AKT, coupled with the evolving multifocal spatial heterogeneity, further complicate the role of AR signaling in CRPC treatment resistance. Innovations in single-cell and spatial technologies reveal tumor heterogeneity and lineage plasticity governed by genetic and epigenetic alterations. Current therapeutic innovations, including approaches such as CYP11A1 inhibition, targeting of the AR N-terminal domain, and bipolar androgen therapy, are showing promise in clinical trials. Overcoming CRPC effectively requires cotargeting androgen/AR-associated pathways and suppressing lineage plasticity through dynamic monitoring and precision interventions.

Hypoxia promotes oral squamous cell carcinoma (OSCC) progression by disrupting redox equilibrium; however, how tumor cells precisely calibrate prosurvival reactive oxygen species levels remains unclear. This study identifies a hypoxia-inducible signaling axis centered on the posttranslational crotonylation of the molecular chaperone heat shock protein 90 alpha family class B member 1 (HSP90AB1), which stabilizes thioredoxin (TXN) to constrain oxidative stress. Hypoxia triggered the hypoxia-inducible factor-1α (HIF-1α)-dependent transcriptional up-regulation of acyl-CoA oxidase 1 (ACOX1), increasing the level of crotonyl-CoA to drive the site-specific crotonylation of HSP90AB1 at lysine 265 (K265cr). Molecular dynamics simulations revealed that K265 crotonylation induced the conformational compaction of HSP90AB1, strengthening its interaction with TXN and enhancing its stability. This chaperone–client axis effectively buffers reactive oxygen species to protumorigenic thresholds, promoting proliferation and conferring cisplatin resistance. Clinically, HIF-1α/ACOX1/HSP90AB1 K265cr/TXN pathway activation is correlated with advanced disease and reduced survival in OSCC patients. Crucially, the HSP90AB1 K265R mutation or pharmacological inhibition of ACOX1 (10,12-tricosadiynoic acid) or TXN (1-methyl-propyl 2-imidazolyl disulfide, PX-12) synergizes with cisplatin to suppress tumor growth in vivo by disrupting redox adaptation. These findings reveal that crotonylation is a hypoxia-sensitive rheostat for TXN-mediated redox control, suggesting that the ACOX1–HSP90AB1–TXN axis is a therapeutic vulnerability in therapy-resistant OSCC.

The past decades have witnessed the rapid development of metamaterial or metasurface cloaks, with different kinds of fascinating invisibility in phase-amplitude restoring. However, available cloaks realized thus far belong to contact-based framework; namely, they should adhere to the targets rather than being apart from each other with arbitrary distance (termed noncontact ones hereafter), which suffered from several critical shortcomings in practice. Here, we first briefly summarized some of the most important milestone works toward contact-based cloaks and then cast a holistic outlook for the conceptual noncontact stealth framework using supportive reconfigurable intelligent surface (SRIS) cloaks. Such transformative paradigm is typically composed of several SRISs deployed far away from the targets, and equipped with artificial intelligence in terms of various microcomputers, sensors, and actuators. The disruptive cloak framework full of cutting-edge techniques such as multidimensional perception, integrated radiation and scattering, and integrated sensing and communication promises to afford a brand new avenue and platform for next-generation invisibility due to their unprecedented flexibility, adaptability, and empowerment of future cloaks in interdisciplinary fields.

Female reproductive disorders influence women’s physical and mental well-being, and the sustainability of the family. However, it is unclear whether lifestyle factors, including sedentary behaviors and physical activity, could impact them. Here, we performed sex-stratified genome-wide association studies of 5 lifestyle factors in European participants from UK Biobank, including self-reported leisure screen time (LST), sedentary behaviors at work and during commuting, time spent in driving, and daily physical activity. We identified 18 novel sex-stratified variants associated with these exposures and showed that LST was more heritable in women (8.6%) than in men (6.9%). Mendelian randomization (MR) analyses using women-related instruments on 4 female reproductive outcomes demonstrated that per 1-h longer LST a day was robustly associated with elevated risks of menorrhagia (odds ratio [OR] = 1.31, 95% confidence interval [CI] = 1.10 to 1.55), endometriosis (OR = 1.34, 95% CI = 1.11 to 1.60), polycystic ovarian syndrome (OR = 3.05, 95% CI = 1.65 to 5.65), and ectopic pregnancy (OR = 1.35, 95% CI = 1.11 to 1.65), while little evidence was found for sedentary behaviors at work or during commuting. Mediation MR showed that the associations with these outcomes were independent from body mass index, except polycystic ovarian syndrome. Nonlinear MR suggested that LST ≥4 h/day was robustly associated with increased risks of endometriosis and menorrhagia. The findings were independently validated using additional genetic data from the European population and survey data from the National Health and Nutrition Examination Survey. In summary, a simple and actionable lifestyle modification, sitting less, is likely to have independently beneficial influences on multiple reproductive disorders.

Aberrant expression or dysfunction of ribonucleoprotein (RNP) granules usually contribute to cancer initiation, progression, and therapeutic response. In the process, protein modification importantly mediates the interactions between cancer and RNPs/associated proteins. Therefore, we tried to summarize and discuss the complex interactions between RNPs and various protein modifications in cancers, facilitating the clinical translation of RNP-based therapies. Studies have shown that RNPs can directly undergo phosphorylation, ubiquitination, SUMOylation, methylation, crotonylation, and acetylation, but no studies have reported glycosylation, fucosylation, or PARylation on RNPs. These modifications can competitively occur on RNPs, affecting the RNP granule expression and function. Cancer cells, immune cells, and stromal cells can undergo RNP granule modifications, consequently mediating current treatment efficacy. These results provide the basis of RNP granule-based antitumor therapy. However, the structural complexity of RNPs and limited research depth pose significant key for clinical translation.

The maintenance and regulation of cancer stem cell (CSC) stemness are crucial for tumor progression; however, the mechanisms underlying tumor stemness regulation remain poorly understood. Herein, we discovered that the enhanced hypoxia-induced transforming growth factor beta induced protein (TGFBI) in bladder cancer (BLCA) promotes the establishment of a stemness loop in the tumor microenvironment, facilitating the maintenance of CSC stemness and malignant proliferation. Clinically, the upregulation of hypoxic TGFBI in BLCA correlates with malignant BLCA features and poor prognosis. Mechanically, TGFBI can stabilize the structural integrity of disulfide bonds in Cys48 and Cys77 of growth differentiation factor 15 (GDF15), leading to aberrant function activity of GDF15 and secretion. Interestingly, secreted GDF15 consequently not only further upregulates CSC-related gene expression but also induces the activation of cancer-associated fibroblasts through the transforming growth factor beta receptor type 2 (TGFBR2)–transforming growth factor β (TGFβ)–TGFBI self-regulatory feedback loop to promote stemness in BLCA. TGFBI knockdown or GDF15 inhibition results in a decrease in functional proteins associated with stemness maintenance, which suppresses bladder CSCs’ self-renewal and effectively improves the efficacy of chemotherapy. Together, these findings demonstrate the pivotal role of TGFBI in BLCA’s stemness maintenance and BLCA progression, highlighting that the inhibition of the TGFBI/GDF15 axis is a potential therapeutic strategy for the amelioration of cancer chemotherapy.

The overuse and misuse of antibiotics have led to widespread resistance in bacteria, which makes infections difficult to treat. The insufficient prevention measures, limited treatment options, and delayed antibiotic developments call for immediate global actions to discover effective and safe treatments for bacterial infections. Over the past decades, more and more studies have found that bacterial extracellular vesicles (BEVs) secreted by bacteria with nanoscale size, lipid bilayer structure, pathogen-associated molecular patterns, and inherent bioactive substances are the ideal candidates for bacterial infection treatment. Meanwhile, advanced engineering approaches have further endowed these BEVs with more customizable properties to effectively fight against bacterial infections. Herein, the present review begins with an overview of the biogenesis and biocomponents of BEVs to better comprehend their bioactivities against bacterial infections. Their isolation and engineering approaches are then introduced, with an emphasis on the diverse genetic, physical, and chemical strategies to functionalize them with desirable capacities for the optimal treatment of bacterial infections. Recent advances in exploring the natural BEVs as antibacterial and antiadhesion agents, as well as the engineered BEVs as vaccine antigens, vaccine adjuvants, and delivery nanocarriers, are expounded successively. Discussions on the new trend of engineering BEVs as nanoweapons to combat bacterial infections, in terms of advantages and challenges, are provided at the end to expedite these BEV-based therapeutic modalities for bacterial infections from bench to bedside.

Inflammatory arthritis, mainly including rheumatoid arthritis (RA) and ankylosing spondylitis (AS), is a group of chronic progressive autoimmune diseases that destroy joints. T helper 17 (Th17) cells are extensively involved in the joint inflammation as well as bone and cartilage destruction of these diseases. Previously, proviral integration site for Moloney-murine leukemia virus 1 (Pim1) was reported to be involved in various autoimmune diseases by mediating the proinflammatory effects of T cells. However, the pathological effect and the therapeutic potential of Pim1 in inflammatory arthritis remain elusive. The present study demonstrated that Pim1 expression was elevated in CD4⁺ T cells locally and systemically in patients with RA or AS and in 2 mice models of inflammatory arthritis. Conditional knockdown of Pim1 in CD4⁺ T cells (Pim1 cKO) or using the Pim1 inhibitor AZD1208 alleviated the development of inflammatory arthritis in association with decreasing the proportion of Th17 cells. In vitro experiments involving inhibition and overexpression confirmed the promoting effect of Pim1 on Th17 cell differentiation. Mechanistically, Pim1 phosphorylated mitochondrial calcium uptake protein 1 to increase mitochondrial calcium influx, which subsequently activated mitochondrial oxidative phosphorylation and promoted Th17 cell differentiation. Through molecular docking and dynamic simulation, nilotinib, a Food-and-Drug-Administration-approved drug, was identified as a selective substitute for the currently clinically nonapproved Pim1 inhibitors, which impeded Th17 cell differentiation and was well tolerated during the treatment of Pim1 cKO mice and 2 inflammatory arthritis mouse models. Our study contributes to a better understanding of the mechanism through which Pim1 promotes Th17 cell differentiation and advances the clinical application of Pim1 as an effective target for treating inflammatory arthritis.

Conventional metal oxide sensors often suffer from limited long-term stability over an ultrabroad temperature range, primarily due to their single-type active sites and a static electronic configuration. To overcome this limitation, we constructed a dual local electric field (LEF) with a graded electron concentration profile by precisely modulating the local chemical environment of CeO₂. This design introduces a thermally activated electric-field switching mechanism, which enables ultrafast and stable response value toward NO₂ detection from −50 to 800 °C. We demonstrate that at low temperatures, the divergent hybridization between Pt and Ce orbitals leads to a lower thermal activation energy for LEF-1 than for LEF-2. As temperature rises, electron migration from the 4f orbitals of Ce³⁺ to adjacent Ce⁴⁺ weakens LEF-1, whereas thermal activation promotes efficient electron transfer in LEF-2, allowing LEF-2 to dominate at high temperatures and ensuring continuous activity. This relay sensing mechanism sustains rapid response (within 12 s) and long-term stability (over 75 d) at both −50 and 800 °C. This work presents an adaptive sensing mechanism through electron gradient differentiation and thermal-driven field switching, offering a new paradigm for the design of intelligent sensors under extreme conditions.