Apoptosis最新文献

PANoptosis is an inflammatory programmed cell death pathway. It integrates apoptosis, pyroptosis, and necroptosis via PANoptosome complexes, thereby coordinating immune responses and remodeling tumor microenvironment (TME). By overcoming limitations of therapies targeting a single-pathway (e.g., those targeting apoptosis), PANoptosis suppresses cancer progression, reverses drug resistance, and synergizes with radiotherapy through immune activation. Mechanistic insights are driving therapeutic strategies that target key regulators (ZBP1, RIPK3) and disease-specific miRNAs to modulate caspase-dependent and caspase-independent cascades. Its pathological duality—acute hyperactivation in tissue injury versus chronic dysregulation in degenerative diseases—highlights the need for context-dependent modulation. PANoptosis activation shows prognostic biomarker potential and universal therapeutic promise for drug-resistant cancers and inflammatory disorders, though clinical translation remains exploratory. This framework positions PANoptosis as a transformative paradigm bridging cell death dynamics and immune regulation.

The mitochondrial voltage-dependent anion channel-1 (VDAC1) protein plays a central role in regulating mitochondrial metabolism, energy production, and apoptosis. VDAC1 interacts with over 100 proteins across the cytosol, endoplasmic reticulum, plasma membrane, and mitochondrial membranes. These interactions coordinate metabolism, cell death, and signal transduction, integrating mitochondrial and cellular functions. To identify VDAC1 binding sites, we designed a peptide array of 768 peptides from 19 selected VDAC1-interacting proteins. We focused on three partners: GAPDH, gelsolin, and actin. Their VDAC1-binding sequences as peptides interacted with purified VDAC1 and, as cell-penetrating peptides, induced cell death, and elevated intracellular Ca²⁺ and ROS levels. Despite sequence diversity, the peptides converged on enhancing transcription factors p53 and c-Jun, upregulating VDAC1, promoting its oligomerization, and triggering apoptosis. Other effects related to their originated protein’s function include no significant effect of the GAPDH-derived peptide on its catalytic activity, indicating its effects are independent of glycolysis. The gelsolin-derived peptide altered actin organization, increasing filopodia and focal adhesion, and actin-derived peptides reduced actin, gelsolin, and tubulin expression. This study is the first to identify VDAC1 binding sites on 19 interacting partners and to demonstrate their use as cell-penetrating peptides to modulate the VDAC1 network. These findings highlight VDAC1’s multifaceted regulatory role and offer a novel approach for targeting VDAC1-protein interactions for therapeutic purposes.

The mechanism underlying vascular remodeling in pulmonary arterial hypertension (PAH) involves complex interactions among various cell types, with dysregulation of endothelial cells (ECs) homeostasis considered a crucial pathological factor. However, their local cellular changes still need to be fully identified during PAH. This study utilized single-cell RNA sequencing data from the GEO database to analyze lung tissue samples from PAH patients and normal controls, revealing significant heterogeneity in lung ECs and dysregulated metabolic pathways. We identified a significant expansion of capillary ECs in PAH patients, linked to dysregulated angiogenesis and glycolysis-tricarboxylic acid cycle metabolic pathways. Through integrative high-dimensional weighted gene co-expression network analysis (hdWGCNA) and machine learning, we identified SPRY1 as a novel key biomarker in PAH pathogenesis and validated its significant downregulation in a monocrotaline-induced PAH rat model. These findings establish capillary ECs expansion and SPRY1 deficiency as pivotal drivers in PAH pathogenesis, providing a foundation for precise therapeutic targeting.

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Epidermal growth factor receptor (EGFR) overexpression is commonly found in various solid tumors, including non-small cell lung cancer, where it is associated with poor prognosis and resistance to treatment. Despite the availability of EGFR-targeted therapies, overcoming drug resistance remains a challenge. Tumor-homing cell-penetrating peptides can selectively target cancer cells and improve drug delivery. In this study, we evaluated the anticancer potential of EGFR-targeted pro-apoptotic peptides, specifically NRPD-KLAK-H and NRPD-CTMP4-H, designed to enhance internalization and overcome drug resistance in EGFR-positive cancers, and compared their effects with those of the free His-tagged peptides NRPD-H, KLAK-H, and CTMP4-H. MTT assays showed that KLAK-H and NRPD-KLAK-H exhibited the strongest anticancer effects, significantly inhibiting cell growth in A-549 cell line, with IC₅₀ values of 33.3 µM and 40.9 µM, respectively. TUNEL assays suggested that KLAK-H and NRPD-KLAK-H induced apoptosis in the tested cell lines. Immunofluorescence revealed successful internalization of KLAK-H/NRPD-KLAK-H, but poor uptake of CTMP4-H/NRPD-CTMP4-H. The His-tag modification improved peptide internalization, suggesting that short poly-histidine sequences can enhance cellular uptake of pro-apoptotic KLAK-derived peptides, particularly in cancer cells. Although the proposed EGFR-targeted proapoptotic peptides did not show the expected effect, our findings indicate that His-tagged pro-apoptotic peptides, especially KLAK-H, hold promise as potential cancer treatments.

BTB domain and CNC homology 1 (BACH1) has been reported to be a vital regulator of tumor progression. However, methods for targeting BACH1 in cancers have not been fully researched. In this study, we identified BACH1 as a poor prognosis-related factor in patients with GBM. Furthermore, a small-molecule compound, HPPE, was found to interact with BACH1 and inhibit the progression of GBM in vitro and in vivo. Molecular dynamics analysis, molecular docking simulation, MST assay, and co-IP experiments revealed that HPPE principally binds to BACH1 at the bZIP domain on the C-terminus and promotes the competitive binding of BACH1 and TCF-4, thus inhibiting formation of the β-catenin/TCF-4 complex. HPPE incubation inhibited proliferation, promoted apoptosis, and induced G2/M arrest, indicating a potential synergistic effect with temozolomide in GBM cells. RNA-seq, qRT‒PCR, and gene enrichment analyses revealed that the induction of HPPE repressed the Wnt/β-catenin pathway. Further experiments revealed that BTB domain deletion from BACH1 eliminated its ability to interact with TCF-4 and significantly rescued the inhibition of Wnt/β-catenin signaling and the reduction of malignant phenotype induced by HPPE in GBM cells. In vivo experiments revealed that HPPE prolonged the survival time of mice, inhibited Wnt/β-catenin pathway activity and had a synergistic effect with TMZ in a xenograft model. In summary, these findings provide potential combined therapeutic strategies for glioma by targeting the C-terminus of BACH1 and inhibiting the activation of WNT signaling.

Tamoxifen is therapeutically employed for breast and ovarian cancers, and it is also widely utilized to activate Cre recombinase in transgenic mice containing Cre-ERT locus. However, high dose tamoxifen (HDTAM) has been reported to induce many side effects in several organs and tissues. Intestinal stem cells (ISCs) play pivotal roles in sustaining the epithelial homeostasis and intestinal functionality. In this study, we systematically investigated the influences of HDTAM on ISCs and their niche. It was found that HDTAM treatment decreased the body weight and the length of small intestines (SI), damaged the gross and histological morphology of SI. Notably, HDTAM dramatically inhibited the proliferation, differentiation, gene expression of ISCs in vivo and in vitro. RNA-Seq results demonstrated that these changes caused by HDTAM were significantly correlated with the degradation of intestinal fatty acids and the process of fatty acid oxidation. Mechanistically, HDTAM impaired the morphology and function of mitochondria of intestinal epithelial cells, increased the endoplasmic reticulum (ER) contents in Paneth cells. Therefore, we concluded that HDTAM could result in a disruption for the function and homeostasis of ISCs, and the interruption of fatty acid utilization might be responsible for these effects. This study implicates a careful use and evaluation of tamoxifen is in necessity when it’s used for intestinal research.

Intervertebral disc degeneration (IVDD) is a major contributor to lumbar diseases, including low back pain, herniation, and stenosis. Despite significant efforts, there have been limited improvements in treatments to alleviate IVDD. The nucleus pulposus (NP) is a crucial component of the intervertebral disc (IVD), responsible for secreting aggrecan, collagen II, and other extracellular matrix components. Programmed cell death (PCD) of NP cells is believed to play a central role in IVDD. RIPK1 is a key mediator of PCD and recently reported PANoptosis, playing essential role in kidney injury, arteriosclerosis, and acute or chronic inflammation-related diseases. We collected varied degenerated human IVD specimens to examine the expression of RIPK1 and downstream cell death-related markers, including GSDMD, Caspase3, and MLKL, which are indicative of pyroptosis, apoptosis, necroptosis, or the recently denominated PANoptosis. In vitro, we performed RIPK1 knockdown and overexpression to study their effects on IVDD. in vivo, we constructed RIPK1 conditional knockout (CKO) mice to confirm the role of RIPK1 in IVDD. We also utilized a small molecule targeted inhibitor to explore its effects on IVDD in vitro and in vivo. Phosphorylated RIPK1 (p-RIPK1) was significantly increased during IVDD in both human and mouse models. Knockout of RIPK1 effectively alleviated IVDD, as evidenced by the RIPK1 cko mice. Further pathological staining and western blot analysis revealed the overexpression of GSDMD, Caspase3, and MLKL, indicating that RIPK1-mediated PANoptosis plays a crucial role in IVDD. in vitro, overexpression of RIPK1 in NP cells exacerbated PANoptosis and degeneration, while RIPK1 knockdown inhibited these processes. We developed a RIPK1-targeted small molecular inhibitor, compound 3–47, which demonstrated superior efficacy in inhibiting p-RIPK1. Both in vitro and in vivo, 3–47 showed remarkable effects in alleviating IVDD by inhibiting RIPK1-mediated PANoptosis. RIPK1-mediated PANoptosis of NP cells plays a critical role in IVDD. The molecular inhibitor 3–47 could effectively delay IVDD progression in mice, highlighting its therapeutic potential.

Ovarian aging is one of the common diseases in the female reproductive system. It is characterized by complex etiologies, involving multiple factors such as genetics, environment, metabolism, and cellular stress. In recent years, autophagy, a crucial cellular self-degradation and repair mechanism, has received substantial attention for its role in maintaining and deteriorating ovarian function. This review systematically summarizes the molecular mechanisms of autophagy and its regulation, as well as the latest research progress of macroautophagy, chaperone-mediated autophagy (CMA) and mitophagy in ovarian aging. Studies have shown that dysregulation of autophagic pathways is closely associated with decreased oocyte quality and reduced ovarian reserve function. Additionally, signaling pathways such as PI3K, AMPK, and mTOR participate in the process of ovarian aging by regulating autophagic activity. Although numerous studies have revealed the critical role of autophagy in ovarian aging, many issues remain to be resolved, such as the crosstalk mechanisms between different autophagic pathways and the precise spatiotemporal dynamics of the autophagic regulatory network. A deep understanding of the regulatory network of multi-pathway autophagy will provide new insights for developing intervention strategies to delay ovarian aging, holding significant scientific and clinical application value.

Myocardial ischemia–reperfusion injury (MIRI) has a high incidence and is difficult to cure. Studies have shown that mitophagy is the key mechanism. This review systematically summarizes all documented herbal preparations and bioactive monomers targeting mitophagy for MIRI treatment, which may serve as a valuable reference for future research on herbal medicine-mediated mitophagy regulation. We conducted comprehensive literature searches in PubMed, Embase, Web of Science, and CNKI databases using the keywords “cardiovascular diseases,” “mitophagy,” “myocardial ischemia–reperfusion injury,” “herbal medicine,” “mechanism,” and “therapeutic” for studies published within the last five years up to July 2025. Studies on herbal medicine interventions unrelated to mitophagy were excluded. Our analysis reveals that mitophagy plays a crucial role in attenuating the detrimental effects of MIRI. Furthermore, herbal medicine demonstrates therapeutic efficacy in maintaining homeostatic balance of mitophagy during MIRI. Herbal medicines can precisely regulate mitophagy via the PTEN-induced putative kinase 1 (PINK1)-parkin pathway, and modulate the expression of BCL2 interacting protein 3 (BNIP3), FUN14 domain-containing protein 1 (FUNDC1), NIP3-like protein X (NIX). Herbal medicines exert protective effects against MIRI through diverse mechanisms and signaling pathways by targeting mitophagy. While mitophagy represents a promising frontier for future cardiovascular research, current herbal medicine applications remain predominantly confined to animal and cellular models, with only limited clinical translation. The findings presented herein are anticipated to provide clinicians and cardiovascular researchers with valuable therapeutic strategies and novel research directions.