Precisely targeting mitochondria to regulate macrophage fate has emerged as a critical therapeutic paradigm for managing inflammation-related pathologies. Mitochondria, while known for producing ATP, have been increasingly recognized for their critical involvement in immune cell differentiation and activation. As key innate immune effectors, macrophages dynamically adapt to microenvironmental cues through metabolic reprogramming and phenotype polarization, processes fundamentally controlled by mitochondrial homeostasis. Organelle-specific therapeutic advances now position mitochondria-targeted strategies as precision interventions with spatiotemporal advantages over conventional approaches. Crucially, these rationally designed systems demonstrate remarkable potential not only to direct macrophage differentiation toward anti-inflammatory phenotypes but also to reprogram the immune microenvironment concurrently, thereby achieving a breakthrough in precision medicine for inflammatory disorders. This review analyzes mitochondrial homeostasis mechanisms in pathophysiology, establishing design principles for targeted therapies. We classify emerging mitochondrial modulation approaches into indirect regulation and direct targeting, evaluating their impacts on macrophage plasticity and therapeutic efficacy. Critical translational challenges are examined, including single-cell-centric regulation, the complexity of mitochondrial interactions in macrophages, and the inefficiency of traditional trial-and-error strategies. The proposed artificial intelligence (AI)-driven methods such as deep learning-based material design, metabolic network modeling, and advanced small-molecule synthesis can accelerate the development of targeted mitochondrial therapies and enhance clinical feasibility. This synthesis aims to accelerate the development of mitochondrially engineered immunotherapies through rational design principles and standardized evaluation protocols.

Aging, caused by a variety of exogenous stimuli and internal factors, leads to a gradual and irreversible decline in the function of the organism. The aging process involves complex gene regulation, in which transcription factors may play a key role as core regulatory elements. In this study, the single-cell transcriptome of skin revealed homeobox C10 (HOXC10) as a core element in the transcription factor regulatory network associated with skin aging. In vivo and vitro, the expression of HOXC10 was down-regulated in senescent fibroblasts and aging tissues, and overexpressed HOXC10 delayed cell senescence and skin aging. Mechanistically, HOXC10 targeted the promoter region of frizzled 6 (FZD6) to reduce its expression and therefore activated the Wnt/β-catenin signaling pathway to delay aging. Finally, by using the Connectivity Map approach, we explored simvastatin as a functional mimic of HOXC10 and demonstrated its antiaging ability in vitro and vivo. In conclusion, our results establish the role of HOXC10/FZD6/Wnt signals in skin aging and identify simvastatin as a potential therapeutic strategy to delay aging.

Alternative splicing (AS) is the central mechanism of transcriptional regulation and generates diverse splice variants that influence protein structure, function, and intracellular activity. AS plays critical roles in tissue differentiation, organ development, and disease progression. This review focuses on the pivotal roles of AS in bone biology, highlighting its regulatory effects on osteoblasts, osteoclasts, chondrocytes, bone matrix remodeling, and bone remodeling, as well as the involvement of AS-related RNA-binding proteins in these processes. We also emphasize bone-specific AS events and their physiological importance in skeletal development and maintenance. Furthermore, the pathological role of AS is emphasized in bone-related tumors such as osteosarcoma, Ewing sarcoma, and chondrosarcoma. This review also explores aberrant AS mechanisms in bone metastatic cancers, including prostate, bladder, and breast cancers, with an in-depth analysis of their roles in tumor progression and alterations in the bone microenvironment. This review provides a comprehensive perspective on how AS factors, signaling pathways, and mechanical stimulation collaboratively regulate bone cells under both physiological and pathological conditions, paving the way for identifying potential intervention strategies. The mechanisms of AS in other pathological bone conditions, such as osteoporosis, osteoarthritis, and hereditary bone disorders, are also summarized. The potential applications of targeting AS in the diagnosis and treatment of bone diseases are discussed, offering insights into the underlying mechanisms and clinical translational potential.

Osteosarcoma, a primary malignant bone tumor originating from mesenchymal cells, is the most prevalent bone malignancy in children and adolescents. Current standard treatment involves aggressive surgical resection aimed at maximal tumor removal; however, this inevitably creates extensive bone defects that substantially impair patients’ quality of life. Furthermore, the risks of postoperative tumor recurrence and metastasis critically influence therapeutic outcomes. With the continuous advancement of biomaterials, their applications in postsurgical osteosarcoma management have increased substantially. Biomaterial-based strategies are enabling diverse antineoplastic function and bone regeneration strategies. However, previous biomaterial strategies have typically focused on osteogenic or antitumor functions in isolation. The current research frontier is shifting toward developing integrated strategies that simultaneously achieve both effective tumor suppression and functional bone regeneration. This review strategically categorizes these emerging strategies into 3 distinct approaches: (a) Traditional bifunctional strategies: Integrating coloaded osteogenic and antitumor agents within a carrier. (b) Enhanced antitumor bifunctional strategies: Incorporating components or designs that actively boost the potency of the antitumor modality beyond simple codelivery. (c) Temporally controlled sequential strategies: Engineered to perform antitumor and pro-regeneration functions in a defined, sequential order. By critically analyzing the cutting-edge biomaterials employed in these strategies, we assessed their potential for clinical translation, emphasized the ongoing technical barriers, and outlined the challenges for future development.

Osteoarthritic cartilage tissue displays a characteristic imbalance in trace element metabolism closely associated with the production of oxidative stress. This study revealed the pivotal role of iron-overload-triggered and selenoprotein-catalyzed lipid peroxidation in osteoarthritis pathogenesis. Based on this discovery, we innovatively pioneered the integration of Fe²⁺-capturing (attack) nanocatalysts and selenium-enriched (defense) polypeptides (selenomethionine [SeMet]) into a hydrogel platform. Polyvinylpyrrolidone-assembled magnesium hexacyanoferrate (MgHCF) nanoparticles enabled efficient Fe²⁺ chelation to counteract ferroptosis. SeMet utilization by the selenoprotein glutathione peroxidase 4 is required to prevent hydroperoxide-induced ferroptosis. Furthermore, a dynamically cross-linked network was constructed from oxidized hyaluronic acid (OHA) and hyaluronic acid–adipic acid dihydrazide (HA-ADH), enhanced by grafting SeMet onto the OHA chain and encapsulating MgHCF into the polymeric matrix. MgHCF@OHA/HA-ADH/SeMet hydrogels exhibited injectable, self-healing, and sustainable drug release capabilities. The platform promoted the anti-lipid peroxidation process and restored the mitochondrial homeostasis of chondrocytes under inflammatory stimulation via the phosphoinositide 3-kinase/Akt/forkhead box O1 pathway. In vivo investigations showed its anti-inflammatory activity, ferroptosis-inhibiting capacity, and ability to reverse cartilage degeneration. This work establishes a therapeutic paradigm based on trace element synergy, providing a translatable disease-modifying candidate.

Chronic unpredicted mild stress (CUMS) and obesity are well-known risk factors for breast cancer (BC). However, their underlying correlation and potential mechanisms remain unknown. Herein, CUMS was found to promote BC growth and metastasis with increased adipocyte lipolysis, reactive oxygen species (ROS) burst, and mitochondrial fission. Metabolomic analysis identified tryptophan (TRP) as the main responding metabolite, which markedly induced macrophage M2 polarization and CXCL1 expression, and in turn promoted adipocyte lipolysis. Molecular investigation showed that CXCL1 triggered KEAP1 m⁶A demethylation via FTO (fat mass and obesity-associated protein) up-regulation, subsequently reducing NRF2 expression to exacerbate ROS burst and mitochondrial fission. Furthermore, either siCXCL1 or FTO inhibition markedly inhibited CUMS-induced BC progression, accompanied by suppression of adipocyte lipolysis, ROS production, and mitochondrial fission, as well as KEAP1 m⁶A demethylation. Our findings highlight the novel signaling of TRP/TAM/CXCL1 in mediating adipocyte lipolysis underlying CUMS-induced BC progression, and KEAP1 m⁶A demethylation presents a promising therapeutic target.

The synthesis of complex organic macrocycles, particularly large and rigid variants, has long been hampered by low yields, poor selectivity, and arduous purification stemming from stepwise approaches. Sánchez-Naya et al. present a transformative “clip-off” strategy in Science, liberating preformed macrocycles from the pores of designed covalent organic frameworks. By strategically incorporating cleavable bonds into specific covalent organic framework linkers and utilizing precise ozonolysis, near-quantitative yields of macrocycles with ring sizes ranging from 114 to 162 atoms have been achieved. This strategy leverages reticular chemistry to control size and functionality, establishing crystalline frameworks as molecular blueprints.

Modern electrical infrastructure relies heavily on insulation materials. Critical examples include polyimide films in microelectronics, epoxy resins in transformers, silicone rubber on outdoor insulators, and polyolefins in power cables. These solid insulation materials have high resistivity, which provides reliable assurance of the safe operation of equipment and power grids. However, both their production and end-of-life disposal place an important environmental burden. In light of the growing prevalence of sustainability principles and circular economy concepts, researchers and industry experts are re-evaluating every stage of the insulation life cycle. This includes synthesis processes, raw materials, energy consumption, and generation of toxic by-products, alongside performance durability and health impacts during use. Ultimately, disposal or recycling methods must also be considered.

Prostate cancer (PCa) progression is driven by intricate molecular mechanisms involving dysregulated signaling networks and posttranslational modifications of key regulatory proteins. In this study, we identify a novel oncogenic pathway wherein cyclin-dependent kinase 12 (CDK12) physically interacts with and phosphorylates forkhead box A1 (FOXA1) at serine 234 (S234). Phosphorylation at this residue markedly enhances FOXA1 transcriptional activity, leading to up-regulation of downstream targets including murine double minute 2 (MDM2), a critical negative regulator of the p53 tumor suppressor. Mechanistically, this CDK12–FOXA1–MDM2 axis destabilizes p53, attenuates apoptotic signaling, and promotes PCa cell survival and proliferation. Therapeutic targeting of CDK12 using the small-molecule inhibitor THZ531 or RNA interference effectively abrogates FOXA1 phosphorylation, restores p53 stability, reactivates apoptotic pathways, and suppresses tumor growth. Notably, the identification of S234 as a functional phosphorylation site in FOXA1 reveals a previously uncharacterized posttranslational regulatory mechanism in PCa biology. These findings establish the CDK12–FOXA1–MDM2 axis as a pivotal driver of PCa progression and underscore the therapeutic potential of targeting FOXA1 phosphorylation to restore tumor suppressor function and induce apoptosis in PCa. Our work provides a mechanistic framework for developing precision therapies aimed at disrupting this oncogenic cascade in PCa.

The ubiquitous contamination of airborne nanoplastics (<100 nm), particularly polystyrene nanoplastics (PS NPs), has emerged as critical determinant regarding respiratory health. As inhalation exposure represents a primary route of human contact, the pulmonary toxicological profiles of PS NPs remained poorly characterized, with underlying mechanisms lacking. In this study, we systematically investigated the pulmonary toxicological mechanisms of PS NPs for inducing acute–subacute lung injury. PS NPs markedly reduced cell viability of lung epithelial cells (BEAS-2B cells) and macrophages (RAW 264.7 cells) in a dose-dependent manner. Further investigations revealed that PS NPs induced a hierarchical oxidative stress paradigm that redox imbalance triggered by reactive oxygen species (ROS) burst led to the cascade activation of compensatory nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, up-regulation of pro-inflammatory cytokines, mitochondrial dysfunction, and apoptosis. Furthermore, the in vivo toxicities of PS NPs were validated by the acute and subacute pulmonary injury on rodent models, which was characterized by obvious inflammatory cell infiltration and pulmonary fibrosis. These results indicated that hierarchical oxidative stress mediated PS NPs-induced acute–subacute lung injury. This also raised a warning that susceptible individuals with long-term plastic exposure should receive regular pulmonary monitoring.