Interstitial lung disease (ILD) is a potentially fatal adverse effect of anticancer therapy, but comparative ILD reporting associations across antineoplastic agents in sex hormone-sensitive solid tumors (breast, ovarian, and prostate cancers) remain unclear. This study aimed to compare ILD reporting associations among antineoplastic agents used in these malignancies and to provide external clinical context from the published literature. We analyzed FAERS reports of ILD associated with 65 prespecified antineoplastic agents used in patients with sex hormone-sensitive solid tumors. Each drug’s ILD reporting association was evaluated using disproportionality analysis (reporting odds ratios), multivariable regression, and time-to-onset analyses. In addition, we conducted a structured PubMed search through March 15, 2026 for eligible human case reports and case series involving these agents. Among 8,146 FAERS ILD reports, trastuzumab deruxtecan (T-DXd) showed a prominent ILD signal and the highest adjusted reporting association. Some sex hormone-pathway agents, including darolutamide and fulvestrant, also showed elevated ILD reporting associations, and concomitant SHA analyses identified additional signals. Older age and lower body weight were independently associated with ILD reporting. In exploratory complete-case TTO analyses, death-recorded ILD reports showed a shorter median reported TTO than non–death-recorded ILD reports; in FDR-adjusted body-weight–stratified analyses, this pattern was observed in the ≥70 kg subgroup but not in the <70 kg subgroup and should be interpreted as hypothesis-generating. The literature review identified 85 eligible publications comprising 98 case-level records and provided supportive clinical context for the FAERS findings. Overall, ILD reporting associations vary across antineoplastic agents used for sex hormone-sensitive solid tumors, even within the same class. Notably, underemphasized signals were observed for certain SHAs. These findings support early ILD monitoring and attention to patient factors such as age and body weight, while underscoring the need for cautious interpretation and confirmation in prospective and real-world studies.

Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative strategy for targeted protein degradation, yet their clinical translation is hindered by systemic toxicity and poor tumor selectivity, leading to dose-limiting side effects. To overcome these limitations, we designed a multi-stimuli-responsive prodrug that enables tumor-selective activation of PROTACs in response to elevated reactive oxygen species (ROS) and glutathione (GSH) in the tumor microenvironment. By masking the hydroxyl group of the VHL ligand with a ROS/GSH-cleavable thioether-urea linker, we developed a PROTAC prodrug that responds to 1O2, HOCl, H2O2, and GSH-key mediators of oxidative stress in tumors. This proof-of-concept was verified by caging BRD4 and AR PROTAC with a methylene blue fluorophore to yield NZ-BRD and NZ-AR. Upon encountering tumor-associated stimuli, these prodrugs underwent efficient activation, releasing functional PROTACs that selectively degraded BRD4 and AR in prostate cancer cells. Intriguingly, the methylene blue liberated during activation served as a self-amplifying photosensitizer, creating a positive feedback loop that boosted 1O2 generation and further enhanced prodrug cleavage. The synergistic effect between PROTAC-mediated protein degradation and photodynamic therapy led to superior antitumor efficacy of PROTAC prodrugs in vitro and in vivo. Our work establishes a spatiotemporally controlled drug activation paradigm that combines precision protein degradation with ROS-amplified activation, presenting a promising approach to mitigate the systemic toxicity associated with conventional PROTAC therapy.

BACKGROUND:Homologous recombination deficiency (HRD) is an important contributor to genomic instability in breast cancer. This study aimed to characterize the mutational landscape of HRD breast cancer in a Shaanxi cohort and explore its clinicogenomic and immune microenvironment characteristics. METHODS:Gene mutation profiles were analyzed in 130 breast cancer patients, and HRD status were quantified using Genomic Scar Scores (GSS). Multivariate logistic regression was used to identify clinicogenomic factors associated with HRD status. Immunohistochemistry for AR, CD8, and FOXC1 was further performed in tumor samples from 20 triple-negative breast cancer patients with different mutation patterns to evaluate molecular subtype characteristics. RESULTS:The most frequently mutated genes in HRD patients were TP53 (61 cases), BRCA (29 cases; BRCA1: 18, BRCA2: 11), and other genes such as FANCA, PTEN. Tumors harboring comutations of TP53 and BRCA exhibited significantly higher GSS compared with tumors without detectable somatic mutations (82.33 vs. 22.25, P < .001). Among HRD-related triple-negative breast cancer, tumors with germline BRCA mutations alone were predominantly classified as basal-like immunosuppressed, whereas TP53-mutated tumors were mainly immunomodulatory. Tumors with co-occurring germline BRCA and TP53 mutations demonstrated higher CD8⁺ T cell infiltration and were primarily classified as the immunomodulatory subtype. CONCLUSIONS:BRCA and TP53 represent the most common genomic alterations in HRD-associated breast cancer in this cohort. Co-occurring BRCA and TP53 mutations were associated with higher genomic instability and distinct immune-related subtype characteristics in triple-negative breast cancer, highlighting the molecular heterogeneity of HRD-associated tumors.

Poly (ADP-ribose) polymerase (PARP) inhibitors though effective in patients with homologous recombination (HR)-deficient tumors, a large population of patients remain unresponsive, primarily due to either the absence of HR-related mutation or the restoration of HR functionality. RAD51, a critical protein in HR repair signaling that ensures precise DNA lesion repair, represents a promising therapeutic target. Inspired by the clinical success of PARP inhibitors in treating BRCA1/2-mutant cancers and leveraging the potential of proteolysis-targeting chimeras (PROTAC) technology—a method that exploits the cell’s protein degradation machinery to eliminate disease-associated proteins, we generated a small-molecule PROTAC G73. This compound degrades RAD51 in a concentration- and time-dependent manner, effectively mimicking the HR-deficient phenotype by impairing DNA double-strand break (DSB) repair. Furthermore, G73-mediated RAD51 degradation synergizes with the PARP inhibitor olaparib, inducing synthetic lethality and re-sensitizing olaparib-resistant cancers to PARP inhibition. This fully small-molecule-based strategy presents a compelling strategy to overcome resistance to PARP inhibitors, expanding their therapeutic potential beyond patients with HR-deficient tumors.

Background The newly developed large language model (LLM) DeepSeek has shown potential for application in other medical fields. However, few systematic studies have assessed its concordance with international expert consensus or compared its performance with leading models such as Gemini 2.0 Pro and ChatGPT-4o in breast cancer. Materials and methods A total of 139 consensus questions from the 19th St. Gallen International Breast Cancer Conference (SG-BCC) were included into analysis. Each model was trained to answer each consensus question five times. The DeepSeek model was compared with the expert panel consensus in terms of concordance rate, robustness of the answers, Pearson correlation coefficient r for non-binary questions, and absolute proportion difference for binary questions. At the same time, a horizontal comparison was made with the previous LLMs Gemini 2.0 Pro and ChatGPT-4o. Results The overall concordance rate between DeepSeek-V3 and the expert panel consensus was 63.31%, and the average answer robustness (i.e., its self-consistency across repeated queries) of DeepSeek-V3 was 86.69%. In addition, DeepSeek-V3 performed similarly to Gemini 2.0 Pro and ChatGPT-4o in terms of concordance rate of the most frequent answers (p = 0.849). In terms of model robustness, there were significant statistical differences among the models (p < 0.001), with DeepSeek-V3 significantly outperforming Gemini 2.0 Pro (p = 0.005) and ChatGPT-4o (p < 0.001). Conclusions DeepSeek models showed moderate concordance in following the consensus of breast cancer expert panel and showed significant advantages in answer robustness, suggesting that DeepSeek has great application potential in the field of clinical decision-making for breast cancer.

548 Background: Homologous recombination deficiency (HRD) implies the dysfunction of homologous recombination repair at the cellular level. The assessment of HRD status benefits making treatment plans and fertility counseling of breast cancer patients. Standard diagnostic tests for detecting HRD are expensive and not universally available. Methods: We trained a deep learning framework to predict HRD status by integrating routinely collected clinical records and histopathological imaging data, including hematoxylin and eosin (H&E)–stained whole-slide images, from primary breast cancer patients (n = 397) across three independent regional medical centers. The patient cohort was split into a training set (80%) and a validation set (20%). Clinical text as well as whole-slide images were encoded using large language model. This model integrated multimodal representation learning and was applied to generate robust HRD predictions. Results: Across breast cancer cohorts from three independent regional medical centers, the proposed approach demonstrated robust and consistent performance in predicting HRD. The reported AUC of 0.82 (95% CI, 0.79–0.84) represents the mean value over ten independent experiments with different random seeds. Notably, the model achieved a precision of 0.84 and a specificity of 0.92, indicating strong discriminatory power with a tendency towards cautious decision-making. Conclusions: Our model showed promising HRD predictive performance in breast cancers directly from routine multimodal data integrating clinical characteristics, imaging description with pathological slides. The HRD-positive predictions generated by this model show promise for clinical translation.

​Background: The 21-gene assay is recommended to estimate distant recurrence risk and guide adjuvant treatment in hormone receptor-positive (HR+), HER2-negative (HER2-) early breast cancer, but its use is limited by cost and accessibility. We developed and validated an interpretable machine-learning model using routine clinicopathologic and imaging features to predict 21-gene recurrence score (RS) stratification. Methods: In this multicenter study in China, 1052 patients who underwent the 21-gene assay were enrolled from three centers. The development cohort (n=838) was randomly split into training and internal test sets, and patients from two other centers formed an independent external test set (n=214). A prospective cohort (n=62) was used for real-world validation. A separate follow-up cohort (n=341) was used to explore associations between model-predicted RS stratification, distant recurrence-free interval (DRFI), and adjuvant chemotherapy use. Findings: The gradient boosting-based Breast Cancer Distant Recurrence Risk (BDRR) model performed best (AUC 0.853 [95% CI, 0.784-0.915] in the internal test set; 0.822 [0.738-0.899] in the external test set). SHAP identified the Ki-67 labeling index, progesterone receptor positive percentage, and age as the leading contributors. In the prospective cohort, accuracy was 0.871. In the follow-up cohort (median 90.1 months; 34 distant recurrences), sensitivity-targeted thresholds (90%/95%) classified 39.9%/25.8% as predicted low RS, and predicted high RS had shorter DRFI. Specificity-targeted thresholds (90%/95%) classified 30.2%/23.8% as predicted high RS, with higher chemotherapy use in predicted high versus low RS groups (P<0.001). An online calculator was developed. Interpretation: The BDRR model provides robust, interpretable prediction of RS stratification in HR+/HER2- early breast cancer and may serve as a complementary tool for risk stratification and adjuvant chemotherapy decision-making in routine practice.

Loss of chromosome 16q is a recurrent genomic alteration in bladder and prostate cancers and is associated with poor clinical outcomes. However, the mechanisms by which 16q loss contributes to tumor progression remain poorly understood. Here, we identify the deubiquitinase CYLD as a major contributor to genomic instability associated with chromosome 16q deletion. Mechanistically, CYLD stabilizes the 53BP1 regulator TIRR by removing K48-linked polyubiquitin chains, thereby preventing excessive accumulation of 53BP1 at sites of DNA damage and maintaining efficient homologous recombination repair. Loss of CYLD disrupts this regulation, shifting DNA double-strand break repair toward 53BP1-dependent non-homologous end joining, leading to homologous recombination deficiency. Consequently, CYLD-deficient tumor cells exhibit increased sensitivity to PARP inhibitors. Together, these findings establish CYLD as a critical regulator of DNA double-strand break repair pathway choice and suggest that CYLD loss, or chromosome 16q deletion, may serve as a biomarker of genomic instability and a predictor of response to PARP inhibitor therapy.

Background Recent advancements in breast cancer management have focused on de-escalating axillary surgery to minimize morbidity and improve quality of life, without compromising survival outcomes. Prior clinical trials have provided evidence supporting the use of less extensive axillary procedures in patients with favorable characteristics. However, research and evidence regarding optimal axillary lymph node surgical decisions after neoadjuvant systemic therapy (NAS) remain limited. Our study aimed to identify key factors in a real-world setting that predict the feasibility of omitting axillary surgery following NAS in clinically node negative (cN0) and clinically staged N1 (cN1) breast cancer. Methods We retrospectively analyzed 1068 clinical N0-1 breast cancer patients who received NAS followed by surgery. Univariable and multivariable logistic regression analyses were used to identify clinicopathological predictors for: (1) ypN0 after NAS in newly diagnosed cN0 patients, which could guide sentinel lymph node biopsy (SLNB) omission; and (2) ypN0 after NAS in newly diagnosed cN1 patients, which could guide axillary lymph node dissection (ALND) omission. Results In newly diagnosed cN0 patients (n = 302), 274 (90.7%) achieved ypN0. Achieving radiological partial response (rPR) after NAS (odds ratio (OR), 0.27; 95% CI, 0.11–0.65; P = 0.003) was associated with a higher ypN0 rate, suggesting potential for SLNB omission. Conversely, higher clinical T stage (cT3-4) (OR, 3.06; 95% CI, 1.11–8.39; P = 0.030) and estrogen receptor (ER) positivity (OR, 3.94; 95% CI, 1.24–12.54; P = 0.020) were associated with a lower ypN0 rate, indicating a tendency towards retaining SLNB. In newly diagnosed cN1 patients (n = 766), the ypN0 rate was 50.3% (385/766). Human epidermal growth factor receptor 2 (HER2) positivity (OR, 0.34; 95% CI, 0.25–0.48; P < 0.001), achieving rPR (OR, 0.38; 95% CI, 0.24–0.59; P < 0.001), and achieving radiological complete response (rCR) (OR, 0.06; 95% CI, 0.02–0.14; P < 0.001) were associated with a higher ypN0 rate, potentially allowing for selective ALND omission. However, tumors located in the central quadrant (OR, 2.99; 95% CI, 1.05–8.50; P = 0.040), along with ER positivity (OR, 1.82; 95% CI, 1.16–2.84; P = 0.009), progesterone receptor (PR) positivity (OR, 1.67; 95% CI, 1.08–2.56; P = 0.020) and invasive breast carcinoma of special type (IBC-ST) (OR, 2.76; 95% CI, 1.05–7.22; P = 0.039) were associated with a lower ypN0 rate, suggesting caution in omitting ALND. Conclusion For newly diagnosed cN0-1 breast cancer patients undergoing NAS, the post-NAS radiological assessment was a critical factor in guiding axillary surgical management decisions. Furthermore, in newly diagnosed cN1 patients, HER2 positivity was also associated with a higher ypN0 rate, which may inform the omission of ALND.

Objective:The BRAFV600E mutation is one of the most common genetic alterations in papillary thyroid cancer (PTC) and is widely recognized as a factor of poor prognosis. Radioactive iodine (RAI) therapy is recommended after thyroidectomy for patients with high-risk level PTC or distant metastatic PTC. However, the association between BRAFV600E mutation and RAI refractoriness remains controversial and requires additional investigation. This meta-analysis was conducted to evaluate the impact of BRAFV600E mutation on the curative effect of RAI therapy. Materials and methods:Electronic searches for relevant studies were performed in the databases of PubMed, EMBASE, and the Science Citation Index databases, with publication date after January 2005. The 131I uptakes status, response to RAI therapy and recurrence of RAI therapy were extracted and compared using meta-analysis. Results:We included 14 eligible studies incorporating 2890 PTC patients, of which 1966 were patients with BRAFV600E mutation. The pooled analysis indicated that BRAFV600E mutation was strongly associated with the loss of iodine avidity (P = 0.0003) in PTC patients, especially in recurrent individuals (P<0.0001). However, BRAFV600E mutation had no significant association on the clinical response or recurrence rate of RAI therapy (P = 0.27 and P = 0.29, respectively). Conclusion:This meta-analysis confirmed the role of BRAFV600E mutation in deterioration of the ability of RAI uptake but provided insufficient evidence to demonstrate that BRAFV600E mutation might impact the clinical response and recurrence after postsurgical RAI therapy for PTC patients.

Homologous recombination deficiency (HRD) affects breast cancer patients. Treatment guided by multigene testing may be particularly beneficial in HRD patients by using platinum-based drugs and poly ADP-ribose polymerase inhibitor (PARPi). However, the optimal method for HRD testing remains undetermined by guidelines or consensus and economic disparities limit the availability of genetic testing. Prioritizing HRD testing by clinical-genomic characteristics is critical for efficient utilization of healthcare resources and improved treatment accuracy. A total of 93 breast cancer patients who underwent HRD genetic testing were included in the study. According to the machine learning model called genomic scar (GS) HRD was defined as a genomic scar score (GSS) ≥ 50 or with deleterious mutation in the BRCA. Multivariate logistic regression analysis was employed to identify the clinical-pathological factors potentially associated with HRD. Suitable variables were selected to construct a predictive model, and the model’s efficacy was evaluated using the area under the receiver operating characteristic (ROC) curve. Internal validation was performed using bootstrap resampling (500 replicates). Patients harboring pathogenic mutation in BRCA exhibited higher GSS (99.85 vs 36.90). HRD was not detected in 41.75

Cleft palate is one of the most common congenital craniofacial disorders that affects children's appearance and oral functions. Investigating the transcriptomes during palatogenesis is crucial for understanding the etiology of this disorder and facilitating prenatal molecular diagnosis. However, there is limited knowledge about the single-cell differentiation dynamics during mid-palatogenesis and late-palatogenesis, specifically regarding the subpopulations and developmental trajectories of periderm, a rare but critical cell population. Here, we explored the single-cell landscape of mouse developing palates from embryonic day (E) 10.5 to E16.5. We systematically depicted the single-cell transcriptomes of mesenchymal and epithelial cells during palatogenesis, including subpopulations and differentiation dynamics. Additionally, we identified four subclusters of palatal periderm and constructed two distinct trajectories of cell fates for periderm cells. Our findings reveal that claudin-family coding genes and Arhgap29 play a role in the non-stick function of the periderm before the palatal shelves contact, and Pitx2 mediates the adhesion of periderm during the contact of opposing palatal shelves. Furthermore, we demonstrate that epithelial-mesenchymal transition (EMT), apoptosis, and migration collectively contribute to the degeneration of periderm cells in the medial epithelial seam. Taken together, our study suggests a novel model of periderm development during palatogenesis and delineates the cellular and molecular transitions in periderm cell determination.

Ductal carcinoma in situ (DCIS) carries a significant risk of postoperative upgrading to invasive breast cancer (IBC), yet existing prediction models lack validation in Asian populations. This study aimed to develop and validate a population-specific nomogram to preoperatively predict DCIS-to-IBC upgrading in Asian patients. A multicenter retrospective cohort of 465 Asian women diagnosed with DCIS by core needle biopsy (2015–2021) was analyzed. Patients were randomly divided into training (n = 257), internal validation (n = 110), and external validation cohorts (n = 98). Predictors were selected via LASSO regression and multivariable logistic regression. Model performance was assessed using AUC, calibration curves, and decision curve analysis (DCA). An interactive online nomogram was developed for clinical application. Postoperative upgrading occurred in 49.46 https://duancl777.shinyapps.io/dynnomapp/ ) enabled real-time risk stratification. The DCIS–IBC Guide Board is the first Asian-specific model integrating clinicopathological predictors to identify high-risk DCIS patients. It facilitates personalized decisions, such as omitting sentinel lymph node biopsy while reducing overtreatment. Although external validation showed moderate performance, this tool addresses critical population heterogeneity and enhances preoperative risk assessment. Prospective multicenter studies are warranted to optimize generalizability and explore multimodal predictors.

Supplementary Fig. S2. Design and characterization of the BRCA2-targeting peptide PROTAC drug. Related to Fig. 1.

The development of precise molecular biomarkers for breast cancer prognosis holds immense potential to improve treatment outcomes. This study aimed to investigate the role of amino acid metabolism genes as predictive markers for breast cancer prognosis and their association with the immune-tumour microenvironment. By employing advanced machine learning algorithms and bioinformatics analysis techniques, the impact of amino acid metabolism-related genes (AAMRGs) on the immune status and overall survival of patients with breast cancer was examined. An AAMRG-based risk model was established to assess the prognostic significance. Validated risk models (AIMP2, IYD, and QARS1) accurately predicted patient outcomes [1 y: 0.87 (0.96-0.78); 3 y: 0.82 (0.87-0.76); 5 y: 0.80 (0.86-0.75)]. Furthermore, this study revealed evidence suggesting that QARS1 may influence breast cancer cell proliferation through methionine metabolism. This analysis provides valuable insights into the mechanisms of breast cancer, emphasizing the significance of AAMRGs as prognostic biomarkers and potential therapeutic targets for optimizing personalized treatment strategies.

Defects in homologous recombination repair (HR) make cells highly susceptible to PARP inhibitors. However, the limited efficacy of PARP inhibitors in targeting HR wild-type tumors restricts their broad utility in cancer treatment. Clinical trials of PARP inhibitors have revealed greater efficacy in men with metastatic castration-resistant prostate cancer harboring BRCA2 mutations compared with those with mutations in other HR genes. To address this, we developed a peptide-based proteolysis-targeting chimera (PROTAC) drug that specifically targets BRCA2, leading to its degradation in a DDB1-dependent manner. The interaction between DDB1 and BRCA2 facilitated nuclear accumulation of the BRCA2 peptide PROTAC (BPD), thereby promoting BRCA2 degradation in response to DNA damage. Combining BPD treatment with PARP inhibitors promoted cell death in prostate cancer cells and induced tumor regression in animal models. These findings suggest that the development of a PROTAC drug targeting BRCA2 offers a promising strategy in combination with PARP inhibitor therapy for treating cancers without HR defects. This approach holds potential for expanding the therapeutic application of PARP inhibition for prostate cancer management. SIGNIFICANCE:BPD is a peptide-based PROTAC that effectively degrades BRCA2, selectively accumulates in tumor cells, reduces homologous recombination efficiency, and enhances sensitivity to PARP inhibitors in prostate cancer.

Background: Gastrointestinal adenocarcinomas (GIACs) are common malignant tumors with poor prognosis in the world. Ferroptosis, characterized by the accumulation of intracellular iron and lipid reactive oxygen species, emerges as a pivotal process in tumorigenesis and cancer advancement. However, the implications of ferroptosis-related genes in GIAC remain to be elucidated. This study aimed at exploring the potential role of ferroptosis-related genes on the prognosis and treatment of GIAC. Methods: In our study, comprehensive clinical, transcriptomic, and/or genomic data were acquired from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), Genomics of Drug Sensitivity in Cancer (GDSC), and Gene Expression Omnibus (GEO). We formulated a ferroptosis-score within the TCGA cohort through gene set variation analysis (GSVA) and subsequently validated in 4 GEO datasets (GSE84437, GSE17536, GSE103479, and GSE19417). Drug sensitivity and immunotherapy efficacy were analyzed in the GDSC dataset and the PRJEB25780 cohort, respectively. Results: The ferroptosis-score was significantly associated with favorable overall survival both in the training cohort [TCGA: P=0.003; hazard ratio (HR), 0.67, 95% confidence interval (95% CI): 0.52-0.87] and across the four validation cohorts (GSE17536: P=0.03; HR, 0.57, 95% CI: 0.34-0.96; GSE19417: P=0.047; HR, 0.53, 95% CI: 0.28-1.01; GSE84437: P=0.004; HR, 0.68, 95% CI: 0.51-0.90; GSE103479: P=0.03; HR, 0.55, 95% CI: 0.32-0.96). Furthermore, the ferroptosis-score was correlated with activation of the DNA damage repair pathway and resistance to cisplatin. Notably, GIACs with low ferroptosis-scores exhibited heightened expression of immune checkpoint molecules such as programmed death-(ligand) 1 and cytotoxic T lymphocyte antigen-4, elevated densities of tumor-infiltrating CD8+ T cells, and a favorable response to pembrolizumab monotherapy. Conclusions: Our findings delineated the clinical relevance of ferroptosis-related genes in GIACs and demonstrated the potential utility of the ferroptosis-score in predicting prognosis and immunotherapy effectiveness.

As the most prevalent female malignancy worldwide, breast cancer frequently involves axillary lymph node metastasis (ALNM), which critically affects therapeutic algorithms. Current guidelines mandate preoperative ultrasound-guided axillary biopsy for suspicious lymph nodes, potentially exposing some low-risk patients with negative results to invasive risks. To optimize the utilization of biopsy, this study established a multimodal predictive framework that preoperatively assesses axillary lymph node (ALN) status, thereby triaging candidates for ultrasound-guided axillary biopsy. We conducted a retrospective single-center analysis of 703 breast cancer patients who underwent ultrasound-guided axillary biopsy with subsequent definitive surgery at the First Affiliated Hospital of Xi’an Jiaotong University (07/2020–05/2023). Following rigorous application of the inclusion/exclusion criteria, 439 eligible patients were randomized into training (n = 307, 69.9

Supplementary Fig. S4. BPD induces BRCA2 degradation in a DDB1-dependent manner. Related to Fig. 3.