Cell Death & Disease最新文献

Vitiligo is an autoimmune depigmenting disorder in which oxidative stress is considered a critical trigger of innate immune activation. Although keratinocytes are increasingly recognized as key contributors to disease progression, the mechanism by which they sense and propagate oxidative stress signals has remained unclear. Here, we identify mitochondrial DNA (mtDNA) release as a pivotal event linking oxidative stress to immune activation in keratinocytes. We demonstrate that hydrogen peroxide induces a sequential mitochondrial membrane remodeling process, in which mitochondrial permeability transition pore opening precedes oligomerization of the outer membrane channel protein VDAC1, enabling selective mtDNA release under non-apoptotic conditions. Escaped mtDNA acts as a danger signal that concurrently activates the cGAS-STING axis and the NLRP3 inflammasome, driving type I and type II interferon production, chemokine release, and pyroptosis. Importantly, genetic silencing or pharmacological inhibition of VDAC1 with VBIT-4 effectively blocked mtDNA release, suppressed downstream inflammatory cascades, and alleviated depigmentation and CD8⁺ T cell infiltration in a murine vitiligo model. These findings uncover a previously unrecognized mechanism by which keratinocytes transform oxidative stress into autoimmune signaling and highlight VDAC1-dependent mtDNA release as a promising therapeutic target to intercept vitiligo at an early stage.

The induction of DNA double-strand breaks (DSBs) within actively transcribed ribosomal DNA (rDNA) arrays triggers transcriptional suppression and drives nucleolar reorganization, including the formation of nucleolar caps that facilitate the engagement of DSBs with canonical DSB signaling and repair proteins. Although these nucleolar responses are critical for rDNA stability, the components that orchestrate these responses remain unclear. In this study, we identified euchromatic histone-lysine N-methyltransferase 2 (EHMT2) as a novel regulator that is essential for rDNA DSB-induced transcriptional suppression, while functioning independently of ATM-mediated nucleolar responses. We found that EHMT2 is required for the repair of rDNA DSBs and the maintenance of rDNA stability, and its deficiency can result in cellular hypersensitivity to rDNA DSBs. Global proteomic analysis revealed that EHMT2 interacts with MBLAC2 to repress rDNA transcription upon rDNA DSBs. The depletion of EHMT2 or MBLAC2 sensitized colorectal cancer cells to ribosomal stress. Furthermore, we uncovered that EHMT2 promotes colorectal tumorigenesis, revealing a novel mechanistic link between rDNA transcriptional regulation and tumor promotion. Together, our findings established the EHMT2-MBLAC2 axis as a pivotal regulator of mammalian rDNA DSB-induced transcriptional silencing that coordinates rDNA DSB repair and the maintenance of rDNA integrity during nucleolar damage.

EGFR, one of the most successful therapeutic targets, has recently been found to exert a novel function for regulating homologous recombination (HR). Activation of HR is the critical event of treatment failure of PARPi in BRCA1/2 wild-type ovarian cancer (OC). Besides, the antitumor effects of biguanides have also been a focus of attention. Here, we discovered that the new biguanide 4C inhibited HR and sensitized BRCA1/2 wild-type OC cells to PARPi by targeting EGFR. Mechanistically, EGFR promoted nuclear accumulation of both BRCA2 and Rad51, and HR activation by competitively inhibiting the binding of BRCA2 and Rad51 to E3 ubiquitin ligase c-Cbl, thereby reducing cancer cell sensitivity to PARPi following ATM-mediated DNA damage signal transmission from the nucleus to the cytoplasm. Interestingly, EGFR was downregulated by 4C, which in turn enhanced the interaction of BRCA2 and Rad51 with c-Cbl. Consequently, BRCA2 and Rad51 were then ubiquitinated and degraded to inhibit HR and increase the sensitivity of OC to PARPi. Thus, these findings reveal that the combination of 4C with PARPi leading to "synthetic lethality" is an effective strategy for treating BRCA1/2 wild-type OC.

Protein phosphatases are critical for regulating cell signaling, cell cycle, and cell fate decisions, and their dysregulation leads to an array of human diseases like cancer. The dual specificity phosphatases (DUSPs) have emerged as important factors driving tumorigenesis and cancer therapy resistance. DUSP12 is a poorly characterized atypical DUSP widely conserved throughout evolution. Although no direct substrate has been firmly established, DUSP12 has been implicated in protecting cells from stress, regulating ribosomal biogenesis, and modulating cellular DNA content. In this study, we used affinity- and proximity-based biochemical purification approaches coupled to mass spectrometry to identify the zinc finger protein ZNF622 as a novel DUSP12 interactor, which was validated by in cell and in vitro IP assays. Interestingly, ZNF622 binds to the unique zinc-binding domain of DUSP12, which previous reports indicated was important for many of DUSP12's functions within the cell. Prior studies had implicated ZNF622 as a modulator of apoptosis, but it remained unclear if and how ZNF622 participated in the cell cycle and, more so, how it promoted cell death. Using mass spectrometry analyses, we found that overexpression of DUSP12 promoted de-phosphorylation of ZNF622 at Ser¹⁴³. Overexpression of ZNF622, but not Ser¹⁴³ phosphomimetic and phosphorylation-deficient mutants, led to an increase in pre-metaphase mitotic defects while knockdown of DUSP12 also showed mitotic defects in metaphase. Furthermore, knockdown of DUSP12 promoted, while knockdown of ZNF622 suppressed, stress-induced apoptosis. Our results support a model where DUSP12 protects cells from ZNF622 mediated stress-induced apoptosis.

BRAFV600-mutant melanoma relies on hyperactivation of the MAPK/ERK pathway for tumorigenesis, with BRAF/MEK inhibitors (BRAFi/MEKi) improving patient outcomes. However, therapeutic resistance frequently emerges, and male patients show poorer responses and outcomes, partially linked to androgen receptor (AR) overexpression. Here, we uncover a mechanistic link between AR signaling and autophagic resistance in BRAFV600-mutant melanoma. We show that BRAFi treatment upregulates AR expression, which induces cytoprotective autophagy through transcriptional activation of DRAM1, a key autophagy-related gene. Functional studies reveal that AR-driven autophagy confers resistance to BRAFi by enhancing cellular survival under therapeutic stress. Our findings establish AR-regulated autophagy as a critical resistance mechanism and provide preclinical evidence for combining AR-targeting PROTAC degrader ARV110 with autophagy inhibitors to overcome BRAFi resistance.

While ferroptosis induction offers promising avenue for cancer therapeutics, its clinical utility in colorectal cancer (CRC) is limited by pervasive intrinsic resistance mechanisms. Here, we identify Aurora kinase A (AURKA) as a central suppressor of ferroptosis by rewiring cholesterol metabolism. Mechanistically, AURKA phosphorylates and destabilizes its negative regulator SAPS3 at Ser523/524, relieving AMPK suppression. Activated AMPK subsequently inhibits SREBP2 nuclear translocation and DHCR7 transcription, resulting in the accumulation of 7-dehydrocholesterol (7-DHC), a lipid antioxidant that confers ferroptosis resistance. Both genetic and pharmacologic inhibition of AURKA restore ferroptosis sensitivity and enhance chemotherapy efficacy in vitro and in patient-derived xenograft models. Clinically, elevated AURKA expression correlates with poor prognosis and reduced chemotherapy response in CRC patients. These findings delineate a novel AURKA-SAPS3-AMPK-SREBP2 axis that bridges cholesterol homeostasis and ferroptosis evasion, positioning AURKA as a promising therapeutic target for chemosensitization in CRC.

Lung transplant ischemia-reperfusion injury poses a significant challenge in transplantation medicine, often causing severe complications and poor patient outcomes. Our study focused on the role of O-GlcNAcylation of Yes-associated protein 1 (YAP1) in exacerbating this injury by regulating autophagy and mitochondrial autophagy pathways. We found that hypoxia-reoxygenation robustly activated the Hippo-YAP1 signaling pathway, leading to increased damage in lung epithelial cells. Concurrently, autophagy and mitochondrial autophagy levels were significantly upregulated, indicating cellular stress responses. During actual lung transplantation, ischemia-reperfusion resulted in a marked increase in autophagy and mitochondrial autophagy levels, accompanied by elevated tissue damage. Notably, YAP1 played a crucial role in orchestrating these processes, as its knockdown reduced autophagy and mitochondrial autophagy levels under both hypoxia-reoxygenation and ischemia-reperfusion conditions. We further elucidated that OGT-mediated O-GlcNAc modification of YAP1 enhanced its interaction with HIF1α, activating downstream hypoxia-responsive molecules. Knockdown of the key enzyme OGT significantly mitigated autophagy, mitophagy, and associated damage in lung epithelial cells and transplant tissues subjected to hypoxia-reoxygenation and ischemia-reperfusion. These findings reveal the intricate interplay between O-GlcNAcylation of YAP1, HIF1α binding, autophagy activation, and mitochondrial autophagy in driving lung transplant ischemia-reperfusion injury, suggesting potential therapeutic targets for ameliorating its detrimental effects.

The RNA-binding protein FUS is commonly mutated in familial cases of amyotrophic lateral sclerosis (ALS-FUS), where it forms cytoplasmic inclusions. In addition, non-mutated FUS is a constituent component of protein inclusions in approximately 5-10% of cases of frontotemporal lobar degeneration (FTLD). Overexpression of wild-type human FUS is toxic to Drosophila neurons, preventing normal development and shortening lifespan in adults. In this study, we demonstrated that removal of the nuclear localisation sequence (NLS) of FUS, a common consequence of ALS-associated mutations, unexpectedly prevents toxicity in Drosophila models despite inducing FUS cytoplasmic mislocalisation. Using novel flies capable of expressing mGFP-tagged FUS, we found that FUS forms dynamic protein granules in Drosophila nuclei and does not form insoluble aggregates. FUS and other FET-family paralogues interact with the repetitive disordered C-terminal domain (CTD) of the large subunit of RNA polymerase II (Polr2A). Using flies that have variable CTD repeat lengths, we demonstrated that FUS genetically interacts with the Polr2A CTD to induce toxicity. Finally, we demonstrated that this association with Polr2A could be relevant to human disease, finding that inclusion-bearing neurons of individuals with FUS-positive FTLD, but not ALS-FUS, show cytoplasmic mislocalisation of POLR2A (the Polr2A human orthologue). Together, these results imply that FUS can have a nuclear mechanism of toxicity when overexpressed in animal models. This toxicity occurs via interaction with RNA polymerase II and aberrant interaction between FUS and POLR2A may be involved in the pathogenesis of FTLD.

Dysregulated macrophage pyroptosis and impaired mitophagy have emerged as critical drivers of rheumatoid arthritis (RA) progression, yet their upstream regulatory mechanisms remain unclear. Previous studies have demonstrated that ANGPTL2 deficiency aggravates alveolar bone loss in periodontitis, a condition that shares mechanistic similarities with RA in terms of bone destruction. Given the established link between periodontitis and RA, these findings suggest that ANGPTL2 may also play a protective role in RA-related joint pathology. In this study, we demonstrate that ANGPTL2 deficiency worsens joint inflammation, bone erosion, and macrophage pyroptosis in mice with collagen-induced arthritis (CIA). Mechanistically, ANGPTL2 loss impairs mitophagy and promotes mitochondrial dysfunction by inhibiting IGFBP5, leading to sustained NLRP3 inflammasome activation. Intra-articular administration of AAV-Angptl2 restores mitophagy, suppresses pyroptosis, and alleviates RA pathology. These findings identify ANGPTL2 as a key regulator of macrophage mitophagy and suggest its therapeutic potential in RA.Schematic diagram of the mechanism of ANGPTL2 in the treatment of rheumatoid arthritis.