bims-meproc 2026-03-15 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2026–03–15
fourteen papers selected by
Grigor Varuzhanyan, UCLA

THBS2 Promotes Prostate Cancer Malignancy via INHBA-Dependent FAK/PI3K/AKT Signaling Activation.
Key signaling pathways in the development and progression of prostate cancer: The crosstalk between inflammation, autophagy, and pyroptosis.
LSD1 promotes prostate cancer cell proliferation by upregulating PRAC1 expression.
ODC1 Polyamine Metabolism Drives Prostate Cancer via AKT and Splicing.
CSDE1 Drives Glycolysis and the Progression of Prostate Cancer Through RAC1-Dependent RAS/MAPK Activation.
Lipidomic profiling in metastatic prostate cancer captures tumor metabolic rewiring and its modulation by androgen receptor-targeting therapy.
Cereblon (CRBN) inhibits prostate cancer metastasis by negatively regulating 6-phosphogluconate dehydrogenase (6PGD).
Alizarin induces a multidirectional mechanism of anti-cancer action in cervical cancer and prostate cancer cells.
Systematic investigation of zinc finger MYND-type containing 11-mediated alternative splicing reveals notable events in prostate cancer.
Caffeic Acid Derivative MPMCA Inhibits Prostate Cancer EMT and Metastasis by Regulating Transcription Factors Snail and Slug.
Body mass index and prostate cancer incidence: a comprehensive systematic review.
Association Between Dietary Folate and Prostate Cancer Aggressiveness Among African Americans and European Americans.
ROS-Fueled Allies: STAT3, PKM2, and HIF-1α Influencing Energy Metabolism in Hormone-Independent Cancers.
Phase Separation of NFIB Suppresses SLC3A2-Mediated Ferroptosis in Castration-Resistant Prostate Cancer.

Anal Cell Pathol (Amst). 2026 ;2026(1): e3503659

THBS2 Promotes Prostate Cancer Malignancy via INHBA-Dependent FAK/PI3K/AKT Signaling Activation.

Yifeng Yao, Yiyang Guo, Shoulei Liu, Yaojun Li, Shanmiao Chen.

  Prostate cancer (PCa) is a leading malignancy among men, with a growing incidence and mortality rate worldwide. There is a pressing need to identify novel molecular biomarkers and therapeutic targets to improve prognosis and treatment strategies for PCa. We analyzed thrombospondin 2 (THBS2) expression patterns in PCa using The Cancer Genome Atlas (TCGA) datasets and validated findings in clinical tissues and cell lines. Functional assays, including Cell Counting Kit (CCK)-8 proliferation, flow cytometry apoptosis, wound healing, and Transwell invasion, were performed on PCa cell lines with altered THBS2 expression. Bioinformatic analyses were conducted to explore THBS2-related pathways, and protein interactions were examined via STRING and Western blot. THBS2 expression was significantly upregulated in PCa tissues and cell lines and correlated with advanced clinicopathological features and poor prognosis. Overexpression of THBS2 promoted PCa cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while inhibiting apoptosis. Mechanistically, THBS2 interacted with INHBA to activate the focal adhesion kinase (FAK)/PI3K/AKT signaling pathway, facilitating malignant progression. INHBA knockdown reversed the oncogenic effects of THBS2, indicating a synergistic interaction between THBS2 and INHBA in PCa pathogenesis. THBS2 acts as an oncogene in PCa by promoting proliferation, invasion, and EMT via the FAK/PI3K/AKT pathway in cooperation with INHBA. These findings highlight THBS2 as a promising biomarker for PCa.

Keywords:  EMT; FAK/PI3K/AKT signaling pathway; INHBA; THBS2; prostate cancer

DOI:  https://doi.org/10.1155/ancp/3503659
Tissue Cell. 2026 Mar 09. pii: S0040-8166(26)00150-3. [Epub ahead of print]101 103457

Key signaling pathways in the development and progression of prostate cancer: The crosstalk between inflammation, autophagy, and pyroptosis.

Yong Cai, Jun-Bo Liu, Yong Chen, Yi-Mai Yang.

  Prostate cancer is one of the most common malignant tumors of the male genitourinary system, with its incidence and mortality continuing to rise globally. This trend is particularly pronounced once the disease progresses to the castration-resistant stage, where current therapeutic options offer limited efficacy and drug resistance remains a major clinical challenge, severely compromising patient survival outcomes. Therefore, a systematic elucidation of the key biological mechanisms driving prostate cancer progression and therapeutic failure is of urgent clinical relevance for the identification of novel intervention targets.Accumulating evidence indicates that the tumor microenvironment plays a central regulatory role in prostate cancer initiation and progression. Among its components, inflammation, autophagy, and pyroptosis represent highly interconnected biological pathways that are deeply involved in tumor initiation, progression, immune modulation, and the development of therapeutic resistance. However, existing studies have largely focused on individual pathways, lacking a comprehensive understanding of their dynamic interplay and integrated regulatory networks.Chronic inflammation promotes tumor progression through sustained release of pro-inflammatory cytokines and immune cell infiltration, leading to genomic instability and aberrant activation of key signaling pathways. Autophagy exhibits a pronounced context-dependent role in prostate cancer, suppressing tumor initiation while paradoxically enhancing cancer cell survival and resistance under metabolic stress and therapeutic pressure. Pyroptosis, an inflammasome-dependent form of programmed cell death, can either facilitate immune evasion via inflammatory mediator release or activate antitumor immune responses, depending on the cellular and microenvironmental context.Notably, key signaling pathways such as NF-κB, mTOR, and AMPK serve as critical nodes linking inflammation, autophagy, and pyroptosis, collectively shaping the biological heterogeneity of prostate cancer and its response to therapy. A deeper understanding of the interactions and dynamic balance among inflammation, autophagy, and pyroptosis will not only address current gaps in the systemic mechanistic framework of prostate cancer research, but also advance our knowledge of its molecular pathology. Importantly, such insights may provide a solid theoretical foundation for the development of precision therapeutic strategies that concurrently target these pathways, thereby offering new avenues to overcome treatment resistance.

Keywords:  Autophagy; Inflammation; Prostate cancer; Pyroptosis; Signaling pathway; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.tice.2026.103457
Sci Rep. 2026 Mar 10.

LSD1 promotes prostate cancer cell proliferation by upregulating PRAC1 expression.

Yang Liao, Chuan Liu.



Keywords:  LSD1; PRAC1; Proliferation; Prostate cancer; TAK-418

DOI:  https://doi.org/10.1038/s41598-026-42928-8
J Cell Mol Med. 2026 Mar;30(5): e71084

ODC1 Polyamine Metabolism Drives Prostate Cancer via AKT and Splicing.

Jian Ma, Ting Pan, Shengli Sun, Musitapa Mutalifu, Wei Yang, Yue Niu, Peng Chen.

  Prostate cancer is an aggressive disease with limited quantifiable biomarkers. One gene of interest is ODC1, which encodes ornithine decarboxylase, the rate-limiting enzyme converting ornithine to putrescine in polyamine metabolism. Although ODC1 is known to be involved in prostate cancer development, exactly how it drives the disease mechanistically is not fully understood. To explore this, we created a prostate cancer cell model with reduced ODC1 expression and examined its effects on tumour behaviours. Knocking down ODC1 significantly slowed cell growth and movement while increasing cell death. Using RNA sequencing, we identified over one thousand differentially expressed genes, with 565 upregulated and 497 downregulated, primarily linked to angiogenesis and cell adhesion. We also found more than two thousand alternative splicing events connected to cell cycle regulation and protein modification. Notably, genes including CAV1, ITGB1, BNIP3, and YTHDF2 were associated with the AKT signalling pathway, suggesting a functional link between ODC1 activity and cancer progression. These results indicate that ODC1 influences prostate cancer cell behaviour by regulating both gene expression and splicing, particularly affecting pathways involved in angiogenesis, adhesion, and the cell cycle. This points to the AKT pathway and polyamine metabolism as potentially valuable targets for future prostate cancer therapies.

Keywords:  ODC1; alternative splicing; gene expression; polyamine metabolism; prostate cancer

DOI:  https://doi.org/10.1111/jcmm.71084
FASEB J. 2026 Mar 31. 40(6): e71607

CSDE1 Drives Glycolysis and the Progression of Prostate Cancer Through RAC1-Dependent RAS/MAPK Activation.

Zhen Yin, Zefeng Wang, Wei Gong, Zitao Wang, Zongze Li, Lizhe Xu, Jinzhuo Ning, Lei Gao, Tiejun Pan, Weimin Yu, Yu Zhou, Jinbo Sun, Fan Cheng.

  Prostate cancer (PCa) remains a leading cause of cancer-related morbidity and mortality among men, necessitating the elucidation of molecular drivers behind its progression. In this study, we demonstrated that CSDE1 was upregulated in PCa tissues, and its expression was associated with poorer progression-free survival in patients with high Gleason scores. Functional analyses revealed that CSDE1 knockdown reduced PCa cell proliferation, migration, and invasion, while suppressing metabolic activity, as evidenced by reduced extracellular acidification rates (ECAR), oxygen consumption rates (OCR), and lactate production. At the mechanistic level, CSDE1 was found to be associated with RAC1 expression and RAC1-related signaling markers, accompanied by changes in MAPK pathway phosphorylation. Genetic modulation of RAC1 partially reversed the cellular and metabolic effects associated with altered CSDE1 expression, supporting a functional role for RAC1 in CSDE1-associated phenotypes. In addition, CSDE1 expression was accompanied by increased levels of the glycolytic regulators GLUT1 and LDHA, and pharmacological inhibition of MAPK signaling partially attenuated CSDE1-associated glycolytic changes. In vivo models validated the oncogenic role of the CSDE1-RAC1 axis in tumor growth. Together, these findings support CSDE1 as a key driver that enhances RAC1-mediated MAPK signaling and metabolic profiles in PCa, suggesting that CSDE1 may serve as a promising prognostic biomarker and therapeutic target.

Keywords:  CSDE1; RAC1; RAS/MAPK; biomarker; glycolysis; prostate cancer

DOI:  https://doi.org/10.1096/fj.202504006R
Prostate Cancer Prostatic Dis. 2026 Mar 13.

Lipidomic profiling in metastatic prostate cancer captures tumor metabolic rewiring and its modulation by androgen receptor-targeting therapy.

Sara Bleve, Francesco Ravera, Silvia Rodrigues, Filippo Pederzoli, Hubert Pakula, Nicole Brighi, Emilio Francesco Giunta, Giuseppe Schepisi, Alessandra Virga, Giorgia Gurioli, Salvatore Luca Burgio, Giuseppe Nicolo' Fanelli, Lisa M Butler, David M Nanus, Johannes V Swinnen, Pier Vitale Nuzzo, Cristian Lolli, Ugo De Giorgi, Massimo Loda.

BACKGROUND: Reprogrammed lipid metabolism with massive upregulation of tumor cell-autonomous synthesis of saturated fatty acids is a hallmark of prostate cancer (PCa) and is driven in part by aberrations in androgen receptor (AR) signaling. While lipid alterations are well described in primary PCa, the extent to which the circulating lipidome reflects tumor-associated metabolic changes in metastatic disease, and its role in therapy response, remains to be determined. This study aims to assess whether plasma lipid profiling captures tumor metabolic rewiring, and whether this reflects response to AR-targeting therapy, in metastatic castration-resistant PCa (mCRPC).
METHODS: Quantitative plasma lipidomics was performed on plasma samples collected from patients with mCRPC (n = 50) and cancer-free subjects (C-FS, n = 14). Samples from patients with mCRPC were collected longitudinally at the time of progression on androgen deprivation therapy prior to initiation of first-line enzalutamide (Enza), after the start of treatment with Enza, before progression on Enza.
RESULTS: Compared to C-FS, patients with mCRPC showed distinct lipidomic signatures, characterized by increased levels of monounsaturated lipids and altered composition of the phospholipid and sphingolipid pool, mimicking the aberrations known to occur in primary PCa tissue. Enza treatment markedly reduced total lipid levels, decreased major phospholipid classes and ceramides, while increasing sphingomyelins. Notably, quantitative differences in specific sphingolipid species occurring after Enza treatment correlated with survival outcomes.
CONCLUSIONS: Plasma lipidomics reflects key metabolic features of PCa and is profoundly impacted by AR inhibition, with prognostic relevance in patients with mCRPC. These findings support its potential as a non-invasive tool for monitoring disease activity and treatment response, and lay the groundwork for lipid-based biomarkers in mCRPC, while indicating that the lipidomic alterations observed may help inform ongoing and forthcoming research on metabolic targeting.

DOI: https://doi.org/10.1038/s41391-026-01100-z
Oncogene. 2026 Mar 09.

Cereblon (CRBN) inhibits prostate cancer metastasis by negatively regulating 6-phosphogluconate dehydrogenase (6PGD).

Koushik Guchhait, Hyeon-Seung Yoon, Hyun-Su An, Seungheon Shin, Hye Seung Nam, Francisco D Yanqui-Rivera, Samara M Oña, Miguel Á Mendez, Jong Yeon Hwang, Daeho Park, Chul-Seung Park, Jee-Young Han, Doo Yong Chung, Seokjae Park, Eun-Kyoung Kim, Su-Geun Yang, Steve K Cho.

Metastasis is the primary cause of mortality in advanced prostate cancer, and the emergence of resistance to androgen receptor (AR)-targeted therapies highlights the urgent need for alternative therapeutic strategies. Metabolic reprogramming has increasingly been recognized as a key driver of metastatic progression. In this study, we uncover a novel tumor-suppressive role for cereblon (CRBN), a substrate receptor of the CRL4CRBN E3 ubiquitin ligase complex, in modulating prostate cancer metastasis through regulation of 6-phosphogluconate dehydrogenase (6PGD), a critical enzyme in the oxidative pentose phosphate pathway (oxPPP). CRBN directly binds a conserved C-terminal α-helix in 6PGD, promoting its polyubiquitination and proteasomal degradation independently of immunomodulatory drugs (IMiDs). Genetic or pharmacological loss of CRBN via CRISPR/Cas9, RNA interference, or PROTAC-mediated degradation stabilized 6PGD and elevated the NADPH/NADP+ ratio. Conversely, re-expression of wild-type CRBN reduced 6PGD levels, restored NADPH/NADP+ ratio, and suppressed cell migration and invasion. Transcriptomic profiling revealed CRBN-induced upregulation of CDH1 and downregulation of the EMT marker MMP1, while CRBN degradation produced the opposite pattern-both effects were reversed by 6PGD inhibition. These regulatory effects were conserved across multiple cancer cell lines and observed in CRBN-deficient mouse tissues. Functional studies using intra-splenic xenograft models further demonstrated that CRBN suppresses metastatic dissemination. Collectively, our findings identify 6PGD as a novel endogenous substrate of CRBN and establish the CRBN-6PGD axis as a critical metabolic checkpoint in prostate cancer metastasis. Therapeutic targeting of this pathway may offer promising strategies for CRBN-deficient or 6PGD-driven cancers.

DOI: https://doi.org/10.1038/s41388-026-03717-9
Sci Rep. 2026 Mar 10.

Alizarin induces a multidirectional mechanism of anti-cancer action in cervical cancer and prostate cancer cells.

Wojciech Trybus, Ewa Trybus, Teodora Król.

  Due to their multifaceted biological effects, anthraquinones have attracted increasing interest as potential anticancer agents. In this study alizarin has been analyzed for its activity against cervical and prostate cancer cell models, which represent malignancies with a high global disease burden. The effects of alizarin were studied in HeLa and DU145 cell lines using both two- and three-dimensional culture systems. Morphological and ultrastructural analyses revealed changes characteristic of apoptosis, accompanied by increased caspase-3/7 activity, phosphorylation of the antiapoptotic protein Bcl-2, activation of ATM and H2A.X in response to DNA damage, inhibition of the PI3K/MAPK signaling pathway, and alterations in mitochondrial morphology associated with elevated reactive oxygen species generation. Alizarin also induced features consistent with mitotic catastrophe and modulated autophagy-related processes. A synergistic proapoptotic effect was observed when alizarin was combined with Venetoclax, a selective Bcl-2 inhibitor, resulting in enhanced cytotoxicity in both cervical and prostate cancer cell models. The antiproliferative effects of alizarin were further associated with inhibition of cell migration, reduction of the mitotic index, and alterations in cell cycle progression, including accumulation of cells in the G2/M phase. Comparable cytotoxic effects were also observed in three-dimensional spheroid cultures. Overall, these findings indicate that alizarin affects multiple cellular pathways involved in cancer cell survival and proliferation and may be of interest in the context of combination anticancer strategies, although further studies are required to clarify the underlying molecular mechanisms.

Keywords:  Alizarin; Apoptosis; Autophagy; Mitotic catastrophe; Oxidative stress; Venetoclax

DOI:  https://doi.org/10.1038/s41598-026-43011-y
Asian J Urol. 2026 Jan;13(1): 24-36

Systematic investigation of zinc finger MYND-type containing 11-mediated alternative splicing reveals notable events in prostate cancer.

Cheng Lian, Zixian Wang, Xu Gao, Gong-Hong Wei.

   Objective: Alternative splicing (AS) is increasingly recognized as a hallmark of cancer, contributing to tumor progression and therapeutic resistance. Zinc finger MYND-type containing 11 (ZMYND11), a critical reader of the histone modification H3.3K36me3, is frequently downregulated in various cancers. However, its specific role in regulating AS in prostate cancer (PCa) remains unclear. This study aimed to elucidate the mechanisms by which ZMYND11 modulates AS in PCa and evaluate its potential as a therapeutic target.
Methods: The comprehensive AS analysis was conducted using two bioinformatics tools, SUPPA2 and rMATS, applied to data from ZMYND11 knockdown PCa cell lines and a large cohort of PCa patient samples. Candidate ZMYND11-mediated AS events were identified based on overlapping results from both tools. Experimental validation was performed in multiple PCa cell lines, and confirmed findings were classified as notable AS events.
Results: SUPPA2, with a threshold of an absolute ΔPSI >0.1 and p-value <0.05, was identified as the optimal tool for detecting ZMYND11-mediated AS events. A total of 19 candidate AS events were identified, with approximately 50% involving exon skipping. Experimental validation highlighted three notable AS events affecting mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), golgin B1 (GOLGB1), and Dmx like 1 (DMXL1). These events are implicated in key pathways influencing tumor growth and metastasis, underscoring the tumor-suppressive role of ZMYND11 in PCa.
Conclusion: This study systematically characterizes ZMYND11-mediated AS in PCa, revealing its pivotal role in modulating splicing events critical to tumor progression. The findings establish ZMYND11 as a potential biomarker and a promising source of novel therapeutic targets for PCa management.

Keywords:  Alternative splicing; Biomarker; Prostate cancer; Therapeutic target; ZMYND11

DOI:  https://doi.org/10.1016/j.ajur.2024.12.002
Cells. 2026 Mar 03. pii: 454. [Epub ahead of print]15(5):

Caffeic Acid Derivative MPMCA Inhibits Prostate Cancer EMT and Metastasis by Regulating Transcription Factors Snail and Slug.

Jo-Yu Lin, Tien-Huang Lin, Yuan-Li Huang, Chao-Yang Lai, Trung-Loc Ho, Chun-Hao Tsai, Yi-Chin Fong, Hsi-Chin Wu, An-Chen Chang, Yueh-Hsiung Kuo, Sung-Lin Hu, Chih-Hsin Tang.

  Prostate cancer (PCa) is the most general cancer in men and is often linked with distant metastasis in its later stages. The caffeic acid (CA) derivative, N-(4-methoxyphenyl)methylcaffeamide (MPMCA), demonstrates superior liver-protective effects compared to CA. Nevertheless, the functions of MPMCA on prostate cancer metastasis remain unclear. Here, we demonstrate that MPMCA blocks migration and invasion in prostate cancer cells without affecting cell viability. By suppressing the production of mesenchymal markers Vimentin, N-cadherin and β-catenin and upregulating the production of the epithelial marker Zonula Occludens-1 (ZO-1), MPMCA also controls Epithelial-Mesenchymal Transition (EMT). The Phosphoinositide 3-kinase (PI3K), Protein kinase B (AKT) and mechanistic target of rapamycin (mTOR) pathway has been documented to regulate MPMCA-inhibited cell motility. Transfection with Snail and Slug cDNA reverses MPMCA's suppression of EMT, migration, and invasion in prostate cancer cells. Importantly, our in vivo data indicates that MPMCA reduces Snail and Slug expression and prostate cancer metastasis. Our evidence suggests that MPMCA is a novel therapeutic candidate for treating metastatic prostate cancer.

Keywords:  EMT; MPMCA; caffeic acid derivatives; prostate cancer; slug; snail

DOI:  https://doi.org/10.3390/cells15050454
Front Oncol. 2026 ;16 1766743

Body mass index and prostate cancer incidence: a comprehensive systematic review.

Dawson Myers, Daniela Chissum Lagos, Isain Zapata, Clara Hwang.

   Introduction: Prostate cancer, the second leading cause of cancer-related mortality among men in the U.S., is projected to cause over 36,000 deaths in 2025. This systematic literature review investigates the association between body mass index (BMI) and prostate cancer incidence, evaluating evidence from 2004 to October 2025.
Methods: A comprehensive search of PubMed using the keywords "BMI" and "prostate cancer" and "screening" identified 60 articles, from which 24 relevant studies were selected for direct analysis.
Results: While some studies show a positive correlation between higher BMI and increased risk of prostate cancer, others report no significant association or an inverse relationship. Thus, the overall evidence supports a neutral relationship between BMI and prostate cancer risk.
Discussion: The review explores potential biological mechanisms linking BMI to prostate cancer, including metabolic dysregulation, hormonal changes, and genetic factors. Additionally, it examines how factors such as age, race/ethnicity, and socioeconomic status may modify this relationship. The review highlights that although a higher BMI is generally associated with increased prostate cancer risk and poorer outcomes, the evidence is inconsistent. Key limitations include high variability in study designs and outcome measures, short follow-up periods as well as studies predominantly from Western populations. These inconsistencies underscore the need for further research to clarify the relationship and improve targeted interventions to mitigate prostate cancer's impact.

Keywords:  BMI; cancer screening; metabolic dysregulation; obesity; prostate cancer

DOI:  https://doi.org/10.3389/fonc.2026.1766743
Nutrients. 2026 Feb 26. pii: 748. [Epub ahead of print]18(5):

Association Between Dietary Folate and Prostate Cancer Aggressiveness Among African Americans and European Americans.

Lihchyun Joseph Su, Sarah O'Connor, Daniela Ramirez Aguilar, MinJae Lee, Harrison Wong, Hui-Yi Lin, Jeannette T Bensen, James L Mohler, Lenore Arab, Longgang Zhao, Ebonee N Butler, Laura Farnan, Susan E Steck.

  Background: Despite the confirmed beneficial effects on preventing neural tube defects, concerns about high intakes of synthetic folate, or folic acid, in promoting cancer progression have been raised. This study evaluated the association between folate intake and prostate cancer (PCa) aggressiveness among African-American (AA) and European-American (EA) males. Methods: This study included 722 AA and 775 EA men with prostate cancer. Folate intake (dietary folate equivalent (DFE), synthetic folate, natural folate) was estimated using the National Cancer Institute Dietary History Questionnaire and detailed dietary supplement use questionnaire. Analyses included univariable comparisons of demographic and clinical characteristics of the two racial groups using the t-test or its non-parametric counterpart, the Wilcoxon test for continuous variables, and the Chi-square test for categorical variables. Logistic regression analysis was performed to evaluate the associations of each source of folate intake with PCa aggressiveness. Interaction effects between folate intake levels and racial groups were tested to evaluate if the association between folate intake and PCa differed by racial groups. Results: A greater proportion of AA subjects were diagnosed with high PCa aggressiveness compared to EAs (31.6% vs. 21.7%; p < 0.001). Both AAs and EAs had associations between decreased DFE intake and PCa aggressiveness after adjusting for covariates. Among AAs, men with the highest quartile levels of synthetic folate intake had higher odds of high-aggressive PCa compared to those with the lowest levels of intake (adj. OR = 1.39; p = 0.27), while the reversed association became stronger among EAs (adj. OR = 0.62; p = 0.14). Conclusions: The association between folate intake and prostate cancer aggressiveness appears to be source-specific and modified by race. These findings highlight the need for population-informed nutritional guidance and further investigation into nutrient-gene and dietary pattern interactions in prostate cancer progression.

Keywords:  folate; prostate cancer; racial disparity; tumor aggressiveness

DOI:  https://doi.org/10.3390/nu18050748
Int J Mol Sci. 2026 Mar 03. pii: 2357. [Epub ahead of print]27(5):

ROS-Fueled Allies: STAT3, PKM2, and HIF-1α Influencing Energy Metabolism in Hormone-Independent Cancers.

Sara Fiorini, Bruno Maras, Giuseppina Mignogna, Monia Perugini, Fabrizio Retali, Giorgia Meschiari, Alberto Macone, Sofia Botta, Fabio Altieri, Margherita Eufemi, Marco Minacori.

  Hormone-independent breast and prostate cancers represent highly aggressive malignancies characterized by profound metabolic reprogramming, elevated oxidative stress, and loss of sensitivity to endocrine therapies. Increasing evidence indicates that tumor progression and metabolic plasticity are sustained by interconnected signaling networks linking transcriptional regulation to energy metabolism. Among these, the STAT3-PKM2-HIF-1α signaling axis, functionally reinforced by reactive oxygen species (ROS), has been proposed as a central regulator of the Warburg phenotype and cellular adaptation to adverse microenvironmental conditions. Using androgen-independent prostate cancer (DU145) and triple-negative breast cancer (KPL-4) cell lines, we demonstrated constitutive activation and reciprocal regulation of STAT3, PKM2, and HIF-1α. Pharmacological inhibition of STAT3, stabilization of tetrameric PKM2 by L-serine, and ROS scavenging with N-acetylcysteine significantly reduced STAT3 phosphorylation, PKM2 nuclear translocation, and HIF-1α stabilization. These molecular effects were accompanied by decreased intracellular ROS levels, reduced lactate production, increased pyruvate levels, and a metabolic shift toward oxidative phosphorylation. Functionally, treated cells exhibited reduced Ki-67 expression and impaired clonogenic capacity. Our results identify the STAT3-PKM2-HIF-1α/ROS axis as a key determinant of metabolic and phenotypic plasticity in hormone-independent breast and prostate cancers, highlighting its potential as a molecular target for therapeutic modulation of cancer-associated metabolic phenotypes.

Keywords:  HIF-1α; PKM2; STAT3; Warburg effect; energy metabolism; hormone-resistant cancer; oxidative stress

DOI:  https://doi.org/10.3390/ijms27052357
Adv Sci (Weinh). 2026 Mar 09. e15340

Phase Separation of NFIB Suppresses SLC3A2-Mediated Ferroptosis in Castration-Resistant Prostate Cancer.

Qiunuo Li, Danyang Chen, Yongzhen Xia, Yili Long, Nan Huang, Rongna Li, Mengting Shi, Mairehaba Kadier, Huafeng Luo, Xiaohui Chen, Hao Liu, Guanmin Jiang.

  Castration-resistant prostate cancer (CRPC) is frequently resistant to conventional therapies and lacks effective treatment options. Although CRPC cells exhibit sensitivity to ferroptosis inducers, the mechanisms regulating ferroptosis remain unclear. Here, we identify nuclear factor I/B (NFIB) as a critical suppressor of ferroptosis in CRPC. NFIB is upregulated in CRPC tissues and cell lines, positively correlating with SLC3A2, a critical subunit of System Xc-. NFIB knockout enhances erastin-induced ferroptosis, marked by elevated Fe2 +, MDA, and ROS levels. Mechanistically, NFIB directly activates SLC3A2 transcription and forms nuclear condensates through intrinsically disordered regions at both the N-terminus (1-69) and C-terminus (173-495), with the C-terminal IDR additionally supporting nuclear localization. Moreover, SIRT7-dependent deacetylation of NFIB regulates acetylation at K65 within the N-terminal IDR, thereby tuning condensate dynamics. K65 mutation reduces condensate liquidity and weakens NFIB-driven SLC3A2 transcriptional activation, resulting in enhanced ferroptosis. In vivo, combined NFIB suppression and ferroptosis induction significantly inhibit tumor growth and increase lipid peroxidation in CRPC xenografts. These findings uncover a critical role of NFIB phase separation and acetylation in ferroptosis regulation and suggest NFIB as a promising therapeutic target in CRPC.

Keywords:  NFIB; SLC3A2; castration‐resistant prostate cancer; ferroptosis; liquid–liquid phase separation

DOI:  https://doi.org/10.1002/advs.202515340