While much attention has been focused on the direct cytotoxic effects of anticancer agents on tumor cells, emerging evidence suggests that the induction of immunogenic cell death (ICD) and the consequent remodeling of the tumor microenvironment may critically influence overall therapeutic efficacy. Sorafenib, a multitargeted tyrosine kinase inhibitor, can induce ferroptosis and thereby trigger ICD, offering the potential to overcome chemoresistance and coordinate systemic antitumor immunity. However, its therapeutic efficacy in colorectal cancer (CRC) remains limited, attributing to its low efficiency in inducing ICD. Herein, this study investigates combined sodium butyrate (NaB) and sorafenib in liposomal co-delivery system (LipNaB@Sor) at an optimal 1:1 M ratio in CRC. LipNaB@Sor synergistically amplifies sorafenib-induced ferroptosis and consequent ICD, concurrently activating antitumor immunity through dendritic cell maturation and cytotoxic CD8⁺ T cell recruitment. Mechanistically, IRF2-mediated Oasl2 downregulation activates the cGAS-STING pathway, augmenting DNA damage signaling cascades. In vivo validation demonstrates significant tumor suppression and prolonged survival without observable toxicity, establishing LipNaB@Sor as a translatable strategy to overcome therapy resistance in immunologically unresponsive CRC.

Aims: Stroke is a major public health concern leading to high rates of death and disability worldwide, unfortunately with no effective treatment available for stroke recovery during the repair phase.Methods: Photothrombotic stroke was induced in mice. Adeno‐associated viruses (AAV) were microinjected into the peri‐infarct cortex immediately after photothrombotic stroke. Grid‐walking task and cylinder task were used to assess motor function. Western blotting, Golgi staining, and electrophysiology recordings were performed to uncover the mechanisms.Results: The ternary complex of neuronal nitric oxide synthase (nNOS), carboxy‐terminal PDZ ligand of nNOS (CAPON) and dexamethasone‐induced ras protein 1 (Dexras1) is structurally beneficial for S‐nitrosylation of Dexras1 (SNO‐Dexras1). In our previous study, uncoupling nNOS‐CAPON interaction by Tat‐CAPON‐12C promoted functional recovery after stroke. Here, we show that ischemia elevated the levels of nNOS‐Dexras1 complex and SNO‐Dexras1 in the peri‐infarct cortex in the days 4–10 after stroke induction, and as excepted, Tat‐CAPON‐12C, a peptide disrupting nNOS‐CAPON interaction, significantly reversed these changes. The above information implies that repressed SNO‐Dexras1 may mediate functional‐promoting effects of Tat‐CAPON‐12C and SNO‐Dexras1 could be the vital molecular substrate for post‐stroke functional recovery in the repair phage. Inhibiting the ischemia‐induced SNO‐Dexras1 by AAV vector‐mediated knockdown of Dexras1 or over‐expression of dominant negative Dexras1 (Dexras1‐C11S) produced sustained recovery of motor function from stroke. In contrast, up‐regulation of SNO‐Dexras1 by over‐expressing Dexras1 worsened stroke outcome. Using electrophysiology recordings, we also observed that silence of Dexras1 in the peri‐infarct cortex increased the spike number and the miniature excitatory postsynaptic currents (mEPSCs) frequency, suggesting enhancement of neuronal excitability. In addition, silence of Dexras1 increased dendritic complexity in cultured neuron and more importantly enhanced dendritic spine density in the peri‐infarct cortex, implying dendritic remodeling.Conclusion: Thus, inhibition of SNO‐Dexras1 positively regulates post‐stroke functional recovery via enhanced neuronal excitability and dendritic remodeling. Our results identify that SNO‐Dexras1 may serve as a novel target for promoting motor functional restoration from stroke in the delayed phase, shedding light on stroke treatment.

While strides in cancer treatment continue to advance, the enduring challenges posed by cancer metastasis and recurrence persist as formidable contributors to the elevated mortality rates observed in cancer patients. Among the multifaceted factors implicated in tumor recurrence and metastasis, cancer stem cells (CSCs) emerge as noteworthy entities due to their inherent resistance to conventional therapies and heightened invasive capacities. Characterized by their notable abilities for self-renewal, differentiation, and initiation of tumorigenesis, the eradication of CSCs emerges as a paramount objective. Recent investigations increasingly emphasize the pivotal role of post-translational protein modifications (PTMs) in governing the self-renewal and replication capabilities of CSCs. This review accentuates the critical significance of several prevalent PTMs and the intricate interplay of PTM crosstalk in regulating CSC behavior. Furthermore, it posits that the manipulation of PTMs may offer a novel avenue for targeting and eliminating CSC populations, presenting a compelling perspective on cancer therapeutics with substantial potential for future applications.