Cell Death and Differentiation最新文献

Prostate cancer is one of the most prevalent malignancies in men, with increasing incidence and mortality largely attributed to treatment resistance and metastasis. The effectiveness of current therapies for advanced cases is hindered by intricate genetic and microenvironmental factors, emphasizing the urgent need for novel therapeutic targets. Chimeric RNAs have emerged as promising biomarkers in cancer research, among which CCDC7_19-13, a circular chimeric RNA, is frequently identified in prostate cancer. Our study reveals that CCDC7_19-13 expression is markedly reduced in advanced and recurrent prostate cancer, where its low levels serve as an independent predictor of poor prognosis. Functional experiments demonstrate that CCDC7_19-13 overexpression inhibits cell proliferation, induces apoptosis, and suppresses tumor growth in vivo, whereas its knockdown reverses these effects. Mechanistically, CCDC7_19-13 encodes a novel protein, CCDC7_241aa, which triggers ferroptosis by interacting with SLC7A11 and facilitating its TRIM21-mediated ubiquitination and degradation. Notably, treatment with recombinant CCDC7_241aa effectively suppresses tumor growth in patient-derived xenograft models without toxicity and enhances the efficacy of docetaxel and enzalutamide in vitro. These findings establish CCDC7_19-13 as a significant prognostic marker and potential therapeutic target in prostate cancer, with the recombinant CCDC7_241aa protein offering promise for combination therapies in advanced cases.

Pyroptosis is strongly associated with refractory epilepsy. However, the underlying mechanisms remain poorly understood. Increasing evidence has shown that long noncoding RNAs (lncRNAs) participate in various neurological disorder processes by regulating programmed cell death. In this study, we identified a novel lncRNA, lncMCL1, by high-throughput screening, which suppresses NLRP3 inflammasome-dependent neural pyroptosis in epilepsy. We demonstrated that lncMCL1 is aberrantly underexpressed in the hippocampus and cortex of epilepsy patients, a phenomenon that was validated in various mouse and rat epilepsy models. Through CRISPR/Cas9, siRNA, and viral manipulation, gain- and loss-of-function experiments confirmed that lncMCL1 inhibits neuronal pyroptosis in vivo and in vitro and exerts antiepileptic effects. Mechanistically, lncMCL1 acts as a scaffold to modulate DDX3X protein stabilization by enhancing NEDD4-mediated DDX3X K48 ubiquitination, thereby inhibiting neural pyroptosis through the suppression of NLRP3 inflammasome signalling. Additionally, IL-18/IL-1β, downstream cytokines of pyroptosis, inhibit lncMCL1 expression through the activation of a shared pathway, the STAT3 pathway, forming a feedback loop. Our findings identify lncMCL1 as a critical regulator of neural cell pyroptosis and a promising therapeutic target for refractory epilepsy.

Long non-coding RNAs (lncRNAs) play crucial roles in diverse mammalian physiological processes, yet their functions in spermatogenesis remain largely underexplored. Here, we identify a unique class of conserved haploid spermatid-associated lncRNAs (cHS-LncRNAs) defined by sequence conservation, testis-restricted expression, and elevated levels in haploid spermatids. Among these, testis-specific conserved lncRNA 1 (Tscl1) is the most highly expressed in round spermatids. Tscl1-null male mice exhibit reduced sperm motility, disorganized mitochondrial sheaths, abnormal fatty acid metabolism, and complete infertility. Mechanistically, Tscl1 directly binds PIWIL1 and HuR via its 5' stem-loop and multiple AU-rich elements, respectively. This interaction promotes assembly of a PIWIL1/eIF3f/HuR/eIF4G3 complex that enhances translation of fatty-acid-metabolism-related mRNAs within the chromatoid body. Notably, TSCL1 variants disrupting the PIWIL1-binding region are significantly enriched in patients with non-obstructive azoospermia (NOA) compared to fertile controls. Collectively, our findings uncover a critical role for Tscl1 in modulating translation during spermiogenesis and implicate TSCL1 as a potential pathogenic locus in human male infertility.

SPOP, the most frequently mutated gene in prostate cancer, has been implicated in the aberrant activation of stress granules, presenting significant challenges in disease management. However, the mechanistic link between SPOP mutations and cellular energy stress remains inadequately explored. In this study, we demonstrate that ULK1 expression is positively correlated with both loss-of-function mutations in SPOP and the upregulation of the E3 ubiquitin ligase TRIM24 in human prostate cancer specimens. Mechanistically, SPOP mutations induce the upregulation of TRIM24, which subsequently binds to ULK1 and catalyzes its non-degradative K27-linked polyubiquitylation. This post-translational modification enhances the stability of ULK1, facilitating cellular adaptation to energy stress and consequently promoting prostate cancer progression. Notably, pharmacological inhibition of TRIM24 using TRIM24-PROTAC (proteolysis-targeting chimera) effectively suppressed tumor growth in mice bearing SPOP-mutant prostate cancer cells. Collectively, these findings elucidate a pivotal role of SPOP mutations in modulating energy stress responses via TRIM24-mediated ULK1 ubiquitylation and underscore the therapeutic potential of targeting TRIM24 in SPOP-mutant prostate cancers.

Energy metabolism is crucial for heart development and function, and dysregulation of this process can lead to heart failure. However, the molecular mechanisms underlying these processes, particularly the role of RNA-binding proteins (RBPs)-mediated posttranscriptional regulation, remain largely unclear. We identified N-acetyltransferase 10 (NAT10) as a key regulator of heart function and cardiac diseases. NAT10 is crucial for heart development, and its dysregulation is associated with heart failure. Cardiac-specific deletion of Nat10 leads to dilated cardiomyopathy, heart failure, and postnatal death by downregulating genes related to fatty acid β-oxidation and heart contraction. Adult-onset knockout Nat10 also results in dilated cardiomyopathy and heart failure. NAT10-deficient hiPSC-CMs also showed impaired calcium transients during contraction. Restoration of NAT10(WT) and NAT10(G641E) (an N-acetyltransferase-inactive mutation), but not NAT10(K290A) (a loss-of-RNA-binding activity mutation), fully rescues the dilated cardiomyopathy, heart failure, and postnatal death phenotypes in Nat10-CKO mice by restoring expression of genes involved in fatty acid β-oxidation and heart contraction. The RNA-binding activity of NAT10 is essential for maintaining the expression of these genes. These findings demonstrate that NAT10 plays a critical role in heart development and function by maintaining the expression of genes related to fatty acid β-oxidation and heart contraction, highlighting its importance in maintaining heart health.

NLRP3 functions as a critical intracellular danger sensor for inflammasome activation, playing a crucial role in autoimmune diseases. Vitiligo progression has been linked to NLRP3, yet its specific involvement in melanocytes of vitiligo remains poorly understood. In this study, we demonstrate that NLRP3 expression is significantly upregulated in the melanocytes of vitiligo patients and melanoma-Treg-induced vitiligo mouse model. Genetic knockout of NLRP3 effectively alleviates vitiligo progression in these mice. Our mechanistic investigations reveal that the downregulation of the E3 ligase β-TrCP1 in vitiligo melanocytes decreases K27-linked ubiquitination levels of NLRP3, which in turn weakens its interaction with the autophagy receptor NDP52. This disruption impairs the selective autophagic degradation of NLRP3, leading to hyperactivation of inflammation and pyroptosis in melanocytes, thereby accelerating vitiligo pathogenesis. Notably, melanocyte-specific knockdown of NLRP3 using lysine-proline-valine (KPV)-modified deformable liposomes (KPV-Lipos) carrying Nlrp3 shRNA significantly alleviates vitiligo development. This study elucidates the mechanism by which autophagy dysfunction mediated excessive NLRP3 inflammasome activation in melanocytes contributes to vitiligo pathogenesis, highlighting potential therapeutic strategies targeting these pathways for the treatment of vitiligo and other pigment-related skin diseases.

Peroxisome proliferator-activated receptor alpha (PPARα) is a crucial transcriptional factor that regulates fatty acid β-oxidation and ketogenesis in response to fasting. However, the mechanisms underlying PPARα function remain unclear. This study identified a novel PPARα-binding protein—RING finger protein 128 (RNF128)—that facilitates PPARα polyubiquitination, resulting in the degradation and suppression of PPARα function during fasting. Furthermore, RNF128 overexpression inhibited fibroblast growth factor 21 expression and lipid metabolism-related genes by facilitating PPARα degradation during fasting. In contrast, silencing RNF128 expression enhanced PPARα-dependent fatty acid β-oxidation and ketogenesis in starved cells. In vivo experiments demonstrated that RNF128 deficiency also significantly reduced lipid levels while increasing fatty acid β-oxidation and ketogenesis during fasting. Adeno-associated virus serotype 8-mediated RNF128 overexpression resulted in increased lipid levels and decreased expression of genes related to fatty acid β-oxidation and ketogenesis in fasted mice. Our findings revealed that RNF128 is crucial for metabolic adaptation to fasting in the liver by interacting with PPARα, thereby enhancing its polyubiquitination and degradation. Therefore, RNF128 is a novel regulator of PPARα function under nutrient-deprived conditions.

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS) characterized by inflammatory demyelination and progressive neurodegeneration. Although current disease-modifying therapies modulate peripheral autoimmune responses, they are insufficient to fully prevent tissue specific neuroinflammation and long-term neuronal and oligodendrocyte loss. Growing evidence implicates various regulated cell death (RCD) pathways, including apoptosis, necroptosis, pyroptosis, and ferroptosis, not only as downstream consequences of chronic inflammation, but also as active drivers of demyelination, axonal injury, and glial dysfunction in MS. These RCD modalities contribute to MS pathology by disrupting cellular homeostasis and sustaining immune activation through the continuous release of damage-associated molecular patterns (DAMPs), thereby establishing a self-amplifying loop between cell death and inflammation. Furthermore, distinct RCD forms can co-occur within lesions, contributing to the complex cellular landscape of MS. This review summarizes current understanding of RCD mechanisms in MS, focusing on their contributions to neuroinflammation and neurodegeneration across different disease stages. We also discuss recent therapeutic advances targeting RCD, including approved drugs whose efficacy may be partially attributed to modulation of cell death, and emerging small-molecule inhibitors targeting key cell death components such as receptor-interacting protein kinase 1 (RIPK1) and NOD-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3). Targeting RCD in conjunction with inflammation may represent a more pragmatic approach for mitigating MS progression and neurodegeneration.

Tongue squamous cell carcinoma (TSCC) is a common oral malignancy prone to metastasis, whose underlying mechanism remains obscure. Here, we report the oncogenic roles of protein arginine methyltransferase 5 (PRMT5) in TSCC via inhibiting transcription factor ΔNp63α. We found that PRMT5 physically interacts with ΔNp63α, resulting in impairment of ΔNp63α-mediated transcriptional regulation. Further investigation revealed that PRMT5 is significantly upregulated in late stages of TSCC and correlated to poor prognosis. On the other hand, inhibition on ΔNp63α contributes to PRMT5-induced migration and metastasis of TSCC cells. Mechanistically, PRMT5 mediates methylation of ΔNp63α at Arg561, which facilitates CDK1-mediated phosphorylation of ΔNp63α and results in weakened DNA binding of this transcription factor. Consequently, ΔNp63α-mediated suppression on cell migration is attenuated in TSCC. Inhibition of PRMT5 efficiently restrain metastasis of TSCC cells in vivo. Our study is helpful to illuminate the molecular mechanism of TSCC metastasis and to provide a new therapeutic strategy for this malignancy.