CCCTC-binding factor (CTCF) is an evolutionarily conserved transcription factor with diverse regulatory roles. Its binding sites exhibit highly ordered nucleosomes and DNA hypomethylation, but how this epigenetic landscape is established remains unclear. In this study, we develop a GpC methylation-assisted tracing (G-MAT) approach to investigate the interplay between DNA methylation and CTCF binding at a base-pair resolution, which reveals that CTCF-chromatin interaction frequently coincides with methylated DNA, which is likely mediated by the nucleosome remodeling and deacetylase (NuRD) complex. We show that NuRD is indispensable for CTCF's chromatin binding, emerging as a regulator of high-order genome architecture. Mechanistically, NuRD facilitates CTCF to interact with TET methylcytosine dioxygenase to maintain adjacent DNA hypomethylation, which is essential for activation of nearby genes. Notably, embryonic stem cells lacking NuRD exhibit impaired lineage commitment. Together, our study unravels a mechanism that elucidates the crosstalk between CTCF binding and the epigenome, with NuRD playing a crucial role as a mediator.

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.

Abstract Heteromeric amino acid transporters (HATs) mediate essential amino acid flux across membranes, but the molecular dynamics of substrate translocation remain poorly defined for many family members. Here, using conventional and adaptive steered molecular dynamics (cMD and ASMD) simulations, we identify residue W230 in the b 0,+ AT transport channel as a dynamic gate that regulates arginine (Arg) influx through side chain flipping. By integrating dynamic network analysis with dynamical cross-correlation of residue motions, we show that regulatory signals propagate from the Arg binding site through transmembrane helix 5 (TM5), a connecting loop, and TM6 to reach W230. We propose a dynamic gating mechanism for b 0,+ AT - mediated amino acid transport. Arg binding at V186 triggers signal propagation that enhances cooperative interactions between W230 and Arg, driving the side chain flipping of W230. Our findings reveal a dynamic gating mechanism underlying b 0,+ AT - dependent Arg transport and suggest that residue-triggered side chain reorientation may represent a conserved and efficient strategy in transporter function. Author Summary Amino acids are the essential building blocks of life, and their transport across cell membranes is vital for nutrition and cellular signaling. Heteromeric amino acid transporters (HATs) mediate this process, yet how they physically move substrates through the protein at the atomic level remains poorly understood. In this study, we used advanced computer simulations to observe, in unprecedented detail, how b 0,+ AT—a key HAT member—transports the amino acid arginine. Our simulations revealed that a single residue, tryptophan 230 (W230), functions as a molecular gate: its side chain flips open to allow arginine to pass and then closes behind it, ensuring one-way traffic into the cell. We further discovered that the initial binding of arginine sends a signal through specific structural elements (helices and loops) to trigger this gate opening. This work not only uncovers a dynamic gating mechanism for b 0,+ AT but also suggests that similar side-chain flipping events may represent a common and efficient strategy used by other transporters to control substrate movement. Our findings provide a new framework for understanding transporter function and could inform future drug design targeting these critical membrane proteins.

Metabolic reprogramming is a hallmark characteristic of renal cell carcinoma (RCC). SIRT3, a key mitochondrial deacetylase, plays a crucial role in metabolic reprogramming. However, its contribution to RCC development remains unclear. Bioinformatics analysis and immunohistochemistry results showed reduced SIRT3 expression in RCC and its correlation with RCC malignancy. SIRT3 knockdown enhanced cell proliferation and colony formation abilities, suggesting that SIRT3 suppresses RCC progression. Mechanistically, knockdown of SIRT3, increases the level of acetylation of isocitrate dehydrogenase 2 (IDH2) at lysine K413 (IDH2K413ac), which impairs its enzymatic activity, mitochondrial function and redox balance. This effect was reversed by the IDH2 acetylation-mimic mutant K413Q but not by the deacetylation-mimic mutant K413R. Honokiol (HKL), a SIRT3 activator, inhibited RCC cell proliferation and colony formation by increasing SIRT3 levels. Our findings identify a novel mechanism by which SIRT3 suppressed RCC progression. SIRT3 acts as a promising therapeutic target for RCC, with HKL as a potential novel therapeutic agent.

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.

Activation of cGAS-STING signaling in cancer cells requires cytosolic DNA produced by intrinsic or treatment-induced DNA damage. However, clinical efforts to exploit this pathway to improve immunotherapy have yielded limited success, highlighting gaps in understanding the link between DNA damage and immunotherapy. Here, we identify ubiquitination-directed cytosolic DNA degradation as a critical determinant for cGAS-STING activation following DNA damage. Mechanistically, the cytosolic DNA exonuclease TREX1 is degraded by the E3 ubiquitin ligase SPOP but is reversely stabilized by the deubiquitinase USP7. Cancer-associated SPOP mutations or USP7 overexpression elevate TREX1 levels, promoting cytosolic DNA degradation and impairing cGAS-STING-mediated immune activation. Notably, elevated USP7 expression correlates with reduced tumor-infiltrating lymphocytes and accelerated disease progression in patients undergoing chemoradiotherapy. Furthermore, USP7 inhibitors reduce TREX1 levels and restore immune responses following radiation. These findings elucidate the mechanisms linking DNA damage to immune activation and highlight USP7 inhibitors as potential enhancers of radioimmunotherapy.

Tyrosine kinase inhibitors (TKIs) including sunitinib and sorafenib remain first-line therapies for advanced renal cell carcinoma (RCC) and lung cancer (LC), but their efficacy is limited by acquired resistance. By characterizing metabolic adaptations in TKI-resistant tumors, we identify ubiquitin-specific peptidase 20 (USP20) as a critical resistance driver that enables cancer cells to evade ferroptosis. We demonstrate TKI-resistant cells upregulate USP20, which binds and deubiquitinates the ferroptosis suppressor GPX4, preventing its proteasomal degradation. Clinically, USP20 and GPX4 are co-overexpressed in RCC and LC patients, correlating with poor prognosis. Mechanistically, USP20 removes K48-linked polyubiquitination on GPX4, sustaining cellular antioxidant capacity. Genetic USP20 ablation sensitizes resistant tumors to TKI-induced ferroptosis. Pharmacological inhibition of USP20 was found to resensitize TKI-resistant tumors to sorafenib, resulting in marked suppression of tumor growth in vivo. Our work uncovers the USP20-GPX4 axis as a druggable linchpin of TKI resistance, revealing ferroptosis evasion as a metabolic vulnerability and proposing a new therapeutic paradigm for overcoming TKI tolerance in RCC and LC.

BACKGROUND:Unc-5 netrin receptor A (UNC5A) activated by protein interacting with C kinase 1 (PICK1) serves as therapeutic target to mitigate the malignant development of prostate cancer (PC). Herein, the mechanism of PICK1/UNC5A axis in PC disease is further investigated. METHODS:Cell functional tests (CCK-8 and Transwell assay) were performed in PC3 and 22Rv1 prostate cancer cell lines to examine how UNC5A/PICK1 overexpression and short hairpin RNA against UNC5A (shUNC5A)/shPICK1 affect PC cell biological functions. Using qRT-PCR and western blot, UNC5A and epithelial-mesenchymal transition (EMT)-related genes and proteins (matrix metallopeptidase 2 (MMP2), MMP9, E-cadherin, and N-cadherin) were measured. How PICK1/UNC5A axis regulates PC cell biology was determined via rescue test. Natural killer (NK) cells were co-cultured with prostate cancer cells, and the effect of PICK1/UNC5A on immune escape of PC was detected by cytotoxicity test, colony formation test and scratch method. RESULTS:UNC5A was lowly expressed in PC cells, with relatively higher expression in PC3 cells and lower expression in 22Rv1 cells. In both cell lines, migration, invasion and EMT of PC cells were promoted by shUNC5A/shPICK1 yet inhibited by overexpressed UNC5A/PICK1. PICK1 could activate UNC5A expression, while suppressing the migration, invasion, EMT and immune escape of PC cells. Moreover, the effects of shUNC5A and shPICK1 were reversed by PICK1 and UNC5A overexpression, respectively, and the converse was also true. CONCLUSIONS:PICK1 hampers the EMT and immune escape of PC cells by activating UNC5A.

4626 Background: SHR-1501, an IL-15 agonist fusion protein composing of a humanized antibody Fc region fused with IL-15 and IL-15Rα sushi domain, demonstrated promising efficacy, well tolerance, and acceptable safety in alone or in combination with BCG in patients with BCG-naive and BCG-unresponsive high-risk NMIBC ( ASCO 2025 ). Here, we report the updated results of this phase 1/2 study (NCT05410730). Methods: In the dose-escalation phase 1a and 1b parts, SHR-1501 monotherapy (200, 400, and 600 μg) or SHR-1501 (600 μg) in combination with BCG (120 mg) was administered to patients with high-risk NMIBC. In the phase 2 part, patients with BCG-naive NMIBC (cohort A), BCG-unresponsive NMIBC carcinoma in situ (CIS; cohort B), and BCG-unresponsive high-grade Ta/T1 NMIBC without CIS (cohort C) were enrolled to receive SHR-1501 (600 μg) plus BCG (120 mg). During the induction phase, all patients received weekly intravesical study treatment for 6 weeks. In the maintenance phase, instillations were administered weekly for three weeks at months 3, 6, 12, 18, and 24 following the initial induction dose. Primary endpoints were dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended phase 2 dose in phase 1a and 1b parts; and was complete response (CR) rate for cohort B and 12-mo disease-free survival (DFS) rate for cohorts A and C in phase 2 part. Results: As of Oct 31, 2025, 112 patients were enrolled (n=8 in phase 1a; n=6 in phase 1b; n=30, 25, and 43 in cohorts A, B, and C in phase 2). The median follow-up duration was 23.0 months (range 3.5-25.6) in patients with BCG-naive NMIBC, 6.5 months (range 2.6-21.2) in patients with BCG-unresponsive NMIBC CIS, and 13.5 months (range 2.5-23.1) in patients with BCG-unresponsive high-grade Ta/T1 NMIBC without CIS. In cohort B, the overall CR rate was 80.0% (20/25), the median DFS was 12.0 months (95% CI 6.0-NR). The 12-mo DFS rate was 90.3% (95% CI, 72.8-96.8) in patients with BCG-naive NMIBC and 62.7% (95% CI, 44.9-76.1) in patients with BCG-unresponsive high-grade Ta/T1 NMIBC without CIS. The 18-mo DFS rates were 90.3% (95% CI, 72.8-96.8) and 58.2% (95% CI, 39.6-72.9), respectively. Treatment-related adverse events (TRAEs) and grade 3 TRAEs occurred in 90 (86.5%) and 19 (18.3%) of 104 patients with SHR-1501 + BCG. The most common TRAEs were urinary tract infection (62.5%) and pollakiuria (35.6%). No TRAEs led to death. Conclusions: This updated analysis confirms the promising efficacy and manageable safety profile of SHR-1501 monotherapy or in combination with BCG in BCG-naive and BCG-unresponsive high-risk NMIBC patients. Two randomized, controlled phase 3 trials are underway in both BCG-unresponsive and BCG-naïve, high-risk NMIBC populations, with the recommended dose of 600 μg SHR-1501 plus BCG. Clinical trial information: NCT05410730 .

PURPOSE: Adrenal myelolipoma (AML) is a benign tumor composed of intermixed adipose and hematopoietic tissues, but its detailed cellular composition remains unclear. CXCL12-abundant reticular (CAR) cells have been found to promote hematopoiesis during AML development; however, the mechanism of adipogenesis in AML remains unclear. This study aimed to characterize the cellular composition of AML and elucidate the potential mechanisms underlying its development, with a particular focus on adipocyte origin. METHODS: Four AML specimens and matched adjacent adrenal tissues were subjected to single-nucleus RNA sequencing, and an additional ten paired samples were analyzed using immunostaining. Complementary in vitro experiments were performed to validate the proposed mechanisms of AML development. RESULTS: Unsupervised clustering revealed that AML is composed predominantly of T cells, B cells, neural-like cells, CAR cells, adipocytes, and nearly all types of myeloid cells. RNA velocity analysis suggested that CAR cells might be the lineage source of adipocytes. Consistently, CAR cells isolated from AML tissues demonstrated adipogenic capacity in vitro. Expression analysis showed high levels of adrenocorticotropic hormone receptor and androgen receptor in adrenal cortical cells and endothelial cells respectively. CellChat analysis further revealed extensive paracrine signals from adrenal cortical cells and endothelial cells to CAR cells. Overexpression of androgen receptor in endothelial cells transcriptionally upregulated key regulators of adipogenesis including COL4A1 and PDGFD. CONCLUSIONS: AML comprises a heterogeneous population of immune and stromal cells, with CAR cells likely serving as the primary source of adipocytes. Moreover, androgen may regulate CAR cells to induce adipocytes via endothelial cells.

PANoptosis is an inflammatory programmed cell death (PCD) pathway integrating pyroptosis, apoptosis, and necroptosis, typically triggered by extrinsic stressors such as pathogen-associated signals. However, whether tumor-intrinsic stress can activate PANoptosis and the underlying regulatory mechanisms remain unclear. Here, we show that sustained and unresolved endoplasmic reticulum (ER) stress induces PANoptosis in renal cell carcinoma (RCC). Mechanistically, inhibition of the E3 ubiquitin ligase RNF25 disrupts eEF1A ubiquitination and degradation, leading to its aberrant accumulation. This accumulation impairs proteostasis and provokes ER stress. When combined with thapsigargin (Tg), which further exacerbates ER stress beyond the adaptive threshold, this sustained and unresolved tumor-intrinsic stress signal triggers PANoptosis. We further identify 3-(Phenylsulfonyl)acrylonitrile (PhSAN) as a selective inhibitor of RNF25 that suppresses its ubiquitin ligase activity and induces ER stress. Notably, the combination of PhSAN and bortezomib (BTZ) drives ER stress, synergistically activating PANoptosis and significantly inhibiting tumor growth in RCC. Our findings establish sustained and unresolved ER stress as a key upstream signal for PANoptosis induction and propose a novel therapeutic strategy for overcoming treatment resistance in RCC through pharmacological inhibition of RNF25 with PhSAN in combination with BTZ.

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.

Tumor metastasis is the primary cause of cancer treatment failure and mortality. Pregnant patients with cancer sometimes experience a poor prognosis and accelerated disease progression, yet the underlying mechanisms remain poorly understood. Here we show that pregnancy enhances tumor metastasis in female mice by elevating adenosine levels, which drives pre-metastatic niche remodeling. Myeloid cells in placental and uterine tissues exhibit increased expression of adenosine-generating enzymes, CD39 and CD73. The accumulated adenosine recruits neutrophils into the tissues of the pre-metastatic microenvironment and upregulates PD-L1 expression on these cells through the cAMP-PKA-NF-κB pathway, thereby suppressing CD8+ T cell function. Consistent with murine models, pregnant women exhibit elevated adenosine levels and increased PD-L1+ neutrophils in peripheral blood, hindering human T cell activation. Inhibiting the adenosine-PD-L1+ neutrophil axis reverses, at least partially, pregnancy-accelerated metastasis without affecting fetal development. These findings shed light on the mechanism of tumor metastasis mice during pregnancy and suggest potential therapeutic targets for treating cancers in pregnant patients.

Bone metastasis is a leading cause of death in prostate cancer (PC) patients. Although androgen deprivation therapy (ADT) combined with novel androgen-targeted agents constitutes the cornerstone of systemic treatment, its efficacy is limited. We investigated the adrenal contribution to promoting progression of castration-resistant PC (CRPC) within bone using a preclinical intratibial xenograft model (VCaP, 22Rv1, and LNCaP cells). Mice underwent orchiectomy (ORX) to mimic ADT, with or without adrenalectomy (ORX + ADX) to eliminate adrenal contribution. A significant increase in bone mineral density (BMD) was observed in tumor-grafted tibiae in ORX-treated mice compared with controls (P < 0.001), indicating a strong tumor-induced sclerotic response. In contrast, ORX + ADX reduced tumor take rate by approximately 50% and decreased tumor-induced BMD by over 80% (P < 0.001). Transcriptomic analysis revealed that ADX downregulated tumor-induced transcripts in bone by over 90%, including osteogenic (Lox, Sparcl1, Bmp2, Postn, and Col1a1) and pro-angiogenic (Bmper, Pecam-1, and Esam) signatures. In addition, BMP, PI3K/Akt, and ERK1/2 signaling pathways were associated with the tumor-induced bone response. Both high serum progesterone and intratumoral levels of dihydrotestosterone (DHT) were associated with the sclerotic bone phenotype. ADX markedly reduced intratumoral DHT and downregulated glycolytic genes (HK2, PFK2, and LDHA) and secretory proteins expressed by the tumor, including stanniocalcin 2, potentially mediating paracrine effects in the sclerotic bone response. Altogether, these findings highlight the critical role of adrenal-dependent androgen synthesis, particularly via progesterone, in driving the sclerotic CRPC in bone. Our findings suggest that a comprehensive blockade of adrenal contribution is essential to prevent the sclerotic bone response associated with CRPC.

154 Background: LIBERTAS is a global phase 3 study evaluating apalutamide (APA) plus intermittent versus continuous androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer (mCSPC). The study aims to determine reduces hot flash burden compared with APA + continuous ADT and whether APA + intermittent ADT provides noninferior radiographic progression-free survival (rPFS). Initial findings demonstrated that treatment with 6 months of APA + ADT resulted in rapid and deep PSA responses in most patients with mCSPC. This abstract presents PSA response results from patients enrolled in China. Methods: Overall, eligible mCSPC participants had ≤3 months of prior ADT, ECOG PS 0–1, and confirmed metastases by conventional or next-generation imaging. All received APA 240 mg/day + ADT during the initial 6-month treatment phase. In the main phase, 22 participants from China with PSA <0.2 ng/mL were randomized 1:1 to continuous or intermittent ADT. Primary endpoints: reduction of hot flash burden, measured by severity-adjusted hot flash score, and rPFS, measured by 18-mo event-free survival rate. Results: In total, 36 participants from China were enrolled from 8 sites, with 22 randomized to the main treatment phase. Median age was 71.0 years (range: 51–79) and median baseline PSA was 64.7 ng/mL (range: 2.6–2399.0). After 3 months of treatment with apalutamide plus ADT, 100.0% of participants achieved a ≥50% PSA decline (PSA50), 94.4% achieved a ≥90% decline (PSA90), and 30.6% achieved PSA <0.2 ng/mL (PSA0.2). Among those who completed the initial 6-month treatment phase, 100% achieved PSA50, 97.2% achieved PSA90, and 61.1% achieved PSA0.2. No new safety signals were observed in the Chinese subgroup. Conclusions: Participants enrolled in the LIBERTAS study had rapid and deep PSA responses to APA plus ADT, with patients in China having a similar rapid and deep PSA decline. The LIBERTAS results confirm the efficacy of APA + ADT in Chinese patients with mCSPC and aligned with the pivotal TITAN Phase 3. The safety profile of APA remained consistent with prior experience, supporting APA’s tolerability in this population. The LIBERTAS study remains on track for results readout in 2027. We would like to acknowledge Todd Simon for his statistical support. Clinical trial information: NCT05884398 .

OBJECTIVES:Patients with homologous recombination repair gene altered (HRR+) metastatic castration-resistant prostate cancer (mCRPC) have a poor prognosis but achieved clinical benefits when treated with first-line niraparib and abiraterone acetate plus prednisone (niraparib + AAP) in the MAGNITUDE trial. We report final exploratory results from MAGNITUDE for the subgroup of patients with Breast Cancer gene-positive (BRCA+) mCRPC enrolled in Asia (NCT03748641). METHODS:Participants with HRR + mCRPC were randomized 1:1 to treatment with niraparib + AAP or placebo + AAP. The primary endpoint of radiographic progression-free survival (rPFS) by blinded independent central review (BICR) and secondary survival endpoints were calculated for the BRCA+ Asian subgroup. Safety was assessed in the Asian HRR+ population. RESULTS:The Asian subgroup included 35 participants with BRCA + mCRPC (all BRCA2+). After 34.99 months of follow-up, median rPFS by BICR was 38.6 months in the niraparib + AAP group versus 8.3 months in the placebo+AAP group (hazard ratio [HR] 0.33, 95% confidence interval [CI] 0.13-0.83, nominal p-value = 0.0141). Clinically relevant benefits were also observed in time to PSA progression (HR 0.32, 95% CI 0.13-0.83), and time to cytotoxic chemotherapy (HR 0.098, 95% CI 0.01-0.68). Median overall survival was not reached in the niraparib+AAP group and was 24.0 months in the placebo+AAP group (HR 0.67, 95% CI 0.27-1.71). The safety profile of niraparib+AAP was consistent with the main study population. CONCLUSIONS:In this final exploratory analysis of the Asian subgroup, participants with BRCA + mCRPC continued to benefit from first-line treatment with niraparib + AAP in comparison to placebo + AAP, with efficacy and toxicity profiles consistent with the global study population. TRIAL REGISTRATION:United States National Library of Medicine (https://clinicaltrials.gov); NCT03748641.

Lipid metabolism is among the most frequently dysregulated metabolic processes in human cancer, yet how cellular lipids, the end products of lipogenesis, and their composition are altered to support various aspects of cancer remains poorly understood. Here, we show that targeting SREBP-dependent lipogenesis via FGH10019, an orally available SREBP inhibitor, enhances docetaxel-induced cytotoxicity in human prostate cancer cells in vitro and in vivo. Mechanistically, suppression of lipid biosynthesis leads to a shift in cellular lipid composition toward polyunsaturated lipids, resulting in increased membrane permeability and intracellular docetaxel accumulation. Thus, our findings reveal a critical role of de novo lipogenesis in protecting cancer cells from chemotherapeutics and suggest that treatment with lipogenesis inhibitors could improve the efficacy of chemotherapy against human prostate cancer.

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