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Programmed Cell Death and Oxidative Stress: 3rd Edition

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 30 January 2026 | Viewed by 12464

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Dr. Takuya Noguchi

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Department of Biopharmaceutical Science, Tohoku University, Sendai 980-8578, Japan
Interests: apoptosis; signaling pathways; phosphorylation; signal transduction; cell signaling; reactive oxygen species; molecular cell biology; cell biology
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Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue “Programmed Cell Death and Oxidative Stress 2.0” (https://www.mdpi.com/journal/ijms/special_issues/94P8FIF763).

Cells that constitute aerobic organisms are continuously exposed to reactive oxygen species (ROS), whose accumulation often initiates oxidative stress. Importantly, oxidative stress plays a critical role in the determination of cell fate by inducing cellular responses, such as proliferation, differentiation, and programmed cell death. Accumulating evidence indicates that oxidative stress initiates various forms of programmed cell death including apoptosis, necroptosis, pyroptosis, parthanatos, and ferroptosis. Moreover, all types of oxidative-stress-induced cell death are closely associated with a wide variety of diseases. For this Special Issue, studies of a wide range of signaling mechanisms and pathological processes related to oxidative stress-induced cell death are welcome.

Dr. Takuya Noguchi
Guest Editor

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Keywords

oxidative stress
programmed cell death
cellular stresses
senescence
cytotoxicity
cancer
neurodegenerative disease
inflammatory disease
organelle stress

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Related Special Issues

Programmed Cell Death and Oxidative Stress in International Journal of Molecular Sciences (9 articles)
Programmed Cell Death and Oxidative Stress 2.0 in International Journal of Molecular Sciences (9 articles)

Published Papers (10 papers)

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Research

Jump to: Review

37 pages, 2142 KB

Open AccessArticle

Nicotine-Induced VEGF Levels in NSCLC Cells Are Modulated by PKA, Hyaluronan, and p53

by Caroline Wozniak, Alvaro Cobos, Aya Sabri, Stuti Goel, Brooke Lopo, Sarah Sarofim, Chanidapa Chutipassakul, Jeffrey Guthrie, Deborah Heyl and Hedeel Guy Evans

Int. J. Mol. Sci. 2025, 26(22), 11103; https://doi.org/10.3390/ijms262211103 - 17 Nov 2025

Viewed by 530

Abstract

Nicotine promotes non-small cell lung cancer (NSCLC) survival in part by elevating vascular endothelial growth factor (VEGF), yet the upstream regulatory mechanisms remain unclear. Here we identify a PKA–HA–p53 regulatory axis that governs nicotine-driven VEGF levels and survival in A549 (p53⁺/⁺) and H1299 (p53-null) cells. Nicotine increased VEGF levels in the media, an effect augmented by protein kinase A (PKA) activation and reduced by PKA inhibition. Blocking hyaluronan (HA) synthesis with 4-methylumbelliferone (4-MU) lowered VEGF levels and diminished the nicotine response, suggesting that HA–CD44 contributes to PKA-linked survival pathways. In A549, p53 inhibition or knockdown enhanced PKA activity and VEGF levels, indicating that p53 constrains this axis; by contrast, H1299 displayed sustained nicotine responsiveness consistent with p53 loss. Pharmacologic nAChR/β-adrenergic blockade blunted nicotine-induced PKA signaling. Functionally, VEGF immunodepletion or co-treatment with a PKA inhibitor, 4-MU, or anti-VEGF antibodies reduced nicotine-supported viability and increased apoptosis, while the addition of purified VEGF rescued survival, establishing the role of VEGF in this pathway. Collectively, these findings delineate a mechanistic network in which PKA, HA–CD44 signaling, and p53 integrate nicotinic cues to control VEGF media levels and cell survival, identifying potential targets (PKA, HA synthesis, VEGF) for mitigating nicotine-mediated NSCLC progression. Full article

(This article belongs to the Special Issue Programmed Cell Death and Oxidative Stress: 3rd Edition)

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17 pages, 3002 KB

Open AccessArticle

The Adaptation of Cancer Cells to Serum Deprivation Is Mediated by mTOR-Dependent Cholesterol Synthesis

by Bayansulu Ilyassova, Nargiz Rakhimgerey, Saule Rakhimova, Nazerke Satvaldina, Asset Daniyarov, Ainur Akilzhanova, Ulykbek Kairov, Dinara Begimbetova and Dos D. Sarbassov

Int. J. Mol. Sci. 2025, 26(22), 10932; https://doi.org/10.3390/ijms262210932 - 12 Nov 2025

Viewed by 617

Abstract

Cancer cells can sustain survival independently of exogenous growth factors. To investigate their adaptation to serum deprivation, we analyzed transcriptomic responses in two cancer cell lines. Transcriptome analysis revealed upregulation of mRNAs encoding cholesterol biosynthesis enzymes. This was a critical adaptive response, as a pharmacological inhibition of the pathway with statin triggered a robust apoptotic cell death accompanied by generation of a mitochondrial reactive oxygen species. The mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cell growth, is known to be engaged in controlling lipid biosynthesis. We detected the high polysomal and preribosomal peaks not only in serum-containing medium but also under serum deprivation, indicating a high rate of protein synthesis and ribosomal biogenesis independent of serum. In addition, the inhibition of mTOR kinase activity substantially reduced polysome abundance, with a more pronounced effect in serum-deprived cancer cells. Notably, the mTOR kinase inhibition also prevented the upregulation of the cholesterol synthesis enzyme that established a direct link between mTOR activity, protein synthesis, and cholesterol biosynthesis. Together, our results show that cancer cells adapt to serum withdrawal by activating the cholesterol synthesis pathway through mTOR-dependent regulation of gene expression and protein synthesis, underscoring a critical mechanism of survival under serum withdrawal. Full article

(This article belongs to the Special Issue Programmed Cell Death and Oxidative Stress: 3rd Edition)

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22 pages, 4823 KB

Open AccessArticle

Investigating the Cytoprotective Mechanisms of the Tardigrade Damage Suppressor (Dsup) Protein in Human Cells Under Hypoxic Stress

by Enxhi Shaba, Claudia Ricci, Lorenza Vantaggiato, Maria Francesca Paolocci, Tommaso Regoli, Kateryna Miedviedieva, Jlenia Brunetti, Valerio Ciccone, Claudia Cecchin, Sandra Donnini, Carlotta Marzocchi, Claudia Landi and Silvia Cantara

Int. J. Mol. Sci. 2025, 26(21), 10452; https://doi.org/10.3390/ijms262110452 - 28 Oct 2025

Viewed by 845

Abstract

Ischemia/reperfusion injury (IRI) is a common damage due to the restoration of blood flow following an ischemic injury. Its pathogenesis is mainly linked to the production of reactive oxygen species (ROS), which sustain cell damage and promote cell death. The tardigrade damage suppressor protein (Dsup) is a DNA-binding protein that enables tardigrades to tolerate stress conditions, including oxidative stress. We investigated the ability of the Dsup to protect human cells from IRI, using an in vitro model of hypoxia and reoxygenation. We exposed HEK293TT cells transfected with the Dsup to hypoxic injury and analyzed cell viability, oxidative stress, expression of antioxidant proteins using functional assays, and a proteomic approach to dissect the molecular mechanisms modulated by the Dsup. Dsup expression significantly enhanced cell survival following hypoxia-reoxygenation and markedly reduced intracellular ROS levels. Proteomic and Western blot analyses revealed a significant upregulation of antioxidant enzymes in Dsup-expressing cells. Furthermore, the Dsup modulated autophagy and key stress-related pathways, including the MAPK cascade. This study demonstrates that the Dsup protects human cells from IRI by reducing oxidative stress and modulating key cytoprotective pathways. Our results establish the Dsup as a promising candidate for future therapeutic applications against IRI, meriting further exploration in in vivo models. Full article

(This article belongs to the Special Issue Programmed Cell Death and Oxidative Stress: 3rd Edition)

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24 pages, 10561 KB

Open AccessArticle

Investigating the Potential of Propranolol as an Anti-Tumor Agent in Colorectal Cancer Cell Lines

by Shiekhah Mohammad Alzahrani, Huda Abdulaziz Al Doghaither, Hind Ali Alkhatabi, Mohammad Abdullah Basabrain and Peter Natesan Pushparaj

Int. J. Mol. Sci. 2025, 26(15), 7513; https://doi.org/10.3390/ijms26157513 - 4 Aug 2025

Viewed by 1364

Abstract

The incidence and mortality of colorectal cancer (CRC) have increased globally. Several therapeutic approaches have been suggested to address this health issue, in addition to classical methods. Propranolol (PRO) is a beta-blocker that was repurposed to treat infantile hemangiomas, and its anti-tumor activity has been reported. This study aimed to investigate the effects of PRO in a panel of CRC cell lines and its potential impact when combined with chemotherapy. The effects of PRO on cell cytotoxicity, cell morphology, colony formation, cell death induction, cell cycle, mitochondrial and intracellular reactive oxygen species (ROS), and migration were measured in all cells. CompuSyn software was utilized to assess the possible synergistic or additive interaction in the combined treatment. The results showed that PRO suppressed cell proliferation, altered cell morphology, inhibited colony formation, induced apoptosis, altered cell cycle and ROS generation, and inhibited the migration of treated cells in a cell-type-specific, time-dependent, and dose-dependent manner compared with the control. HT-29 was the most sensitive cell line to PRO in terms of cytotoxicity, apoptosis, cell cycle arrest, and ROS generation, while SW-480 was the most sensitive in terms of migration inhibition. Moreover, the PRO and capecitabine combination exhibited a synergistic effect and induced mitochondrial apoptosis in metastatic CRC cells. The data suggest that PRO could be a promising adjuvant therapy for primary and advanced CRC. This study identified variations between CRC cell lines in response to PRO, which may be related to their genetic and epigenetic differences. In addition, the findings highlight the potential of combination strategies to improve therapeutic outcomes in metastatic CRC. Full article

(This article belongs to the Special Issue Programmed Cell Death and Oxidative Stress: 3rd Edition)

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16 pages, 2760 KB

Open AccessArticle

Protective Effects of (-)-Butaclamol Against Gentamicin-Induced Ototoxicity: In Vivo and In Vitro Approaches

by Sumin Hong, Eunjung Han, Saemi Park, Kyungtae Hyun, Yunkyoung Lee, Hyun woo Baek, Hwee-Jin Kim, Yoon Chan Rah and June Choi

Int. J. Mol. Sci. 2025, 26(9), 4201; https://doi.org/10.3390/ijms26094201 - 28 Apr 2025

Cited by 3 | Viewed by 1328

Abstract

Gentamicin-induced ototoxicity leads to irreversible sensorineural hearing loss due to structural and functional damage to inner ear hair cells. In this study, we identified (-)-butaclamol as a potent protective agent against gentamicin-induced cytotoxicity through high-content screening (HCS) of a natural compound library. (-)-Butaclamol significantly enhanced cell viability in both HEI-OC1 cells and zebrafish neuromasts, demonstrating robust protection against gentamicin toxicity. Mechanistically, (-)-butaclamol inhibited intrinsic apoptosis, as evidenced by reduced TUNEL-positive cell counts and the downregulation of BAX and caspase-3, alongside the upregulation of BCL-2. Moreover, (-)-butaclamol activated key survival signaling pathways, including AKT/mTOR and ERK, while suppressing the inflammatory regulator NF-κB. Additional analyses revealed that (-)-butaclamol effectively mitigated oxidative stress and restored autophagic activity, as confirmed by CellROX and LysoTracker assays. Notably, TMRE staining showed that (-)-butaclamol preserved mitochondrial membrane potential in zebrafish hair cells, indicating mitochondrial protection. Collectively, these findings suggest that (-)-butaclamol exerts comprehensive cytoprotective effects against gentamicin-induced ototoxicity by modulating apoptosis, enhancing survival signaling, and restoring mitochondrial and cellular homeostasis. These results highlight the therapeutic potential of (-)-butaclamol and provide a foundation for future studies aimed at its clinical application. Full article

(This article belongs to the Special Issue Programmed Cell Death and Oxidative Stress: 3rd Edition)

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17 pages, 5547 KB

Open AccessArticle

The Selective 3-MST Inhibitor I3MT-3 Works as a Potent Caspase-1 Inhibitor

by Kohei Otani, Ryuto Komatsu, Takuya Noguchi, Wakana Suzuki, Yusuke Hirata and Atsushi Matsuzawa

Int. J. Mol. Sci. 2025, 26(5), 2237; https://doi.org/10.3390/ijms26052237 - 2 Mar 2025

Cited by 3 | Viewed by 1765

Abstract

I3MT-3 (HMPSNE) has been identified as a selective inhibitor of the supersulfide-producing enzyme 3-MST. In this study, we found that I3MT-3 inhibits inflammatory responses, including the secretion of the pro-inflammatory cytokine interleukin-1β (IL-1β) and inflammatory cell death pyroptosis, induced by the activation of the inflammasomes composed of NLRP1, NLRP3, or AIM2. However, interestingly, the knockdown of 3-MST did not affect the activation of the inflammasomes, suggesting that the inhibitory effect of I3MT-3 on inflammasome activation is mediated by alternative ways rather than the inhibition of 3-MST. Interestingly, an in vitro caspase assay revealed that I3MT-3 directly inhibits caspase-1 activation, and molecular docking simulations raised the possibility that the pyrimidone ring in I3MT-3 stabilizes direct interaction of I3MT-3 with caspase-1. Taken together, our data suggest that I3MT-3 inhibits inflammasome activation by targeting caspase-1, and show I3MT-3 as a potent inhibitor of caspase-1. Full article

(This article belongs to the Special Issue Programmed Cell Death and Oxidative Stress: 3rd Edition)

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25 pages, 5679 KB

Open AccessArticle

Malvidin-3-O-Glucoside Mitigates α-Syn and MPTP Co-Induced Oxidative Stress and Apoptosis in Human Microglial HMC3 Cells

by Rachit Sood, Sanjay, Sung-Ung Kang, Na Young Yoon and Hae-Jeung Lee

Int. J. Mol. Sci. 2024, 25(23), 12733; https://doi.org/10.3390/ijms252312733 - 27 Nov 2024

Viewed by 2145

Abstract

Parkinson’s disease (PD) is a widespread age-related neurodegenerative disorder characterized by the presence of an aggregated protein, α-synuclein (α-syn), which is encoded by the SNCA gene and localized to presynaptic terminals in a normal human brain. The α-syn aggregation is induced by the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mitochondrial neurotoxin and is therefore used to mimic PD-like pathology in various in vitro and in vivo models. However, in vitro PD-like pathology using α-syn and MPTP in human microglial cells has not yet been reported. Malvidin-3-O-glucoside (M3G) is a major anthocyanin primarily responsible for pigmentation in various fruits and beverages and has been reported to possess various bioactivities. However, the neuroprotective effects of M3G in humanized in vitro PD-like pathologies have not been reported. Therefore, individual and co-treatments of α-syn and MPTP in a human microglial (HMC3) cell line were used to establish a humanized PD-like pathology model in vitro. The individual treatments were significantly less cytotoxic when compared to the α-syn and MPTP co-treatment. This study examined the neuroprotective effects of M3G by treating HMC3 cells with α-syn (8 μg/mL) and MPTP (2 mM) individually or in a co-treatment in the presence or absence of M3G (50 μM). M3G demonstrated anti-apoptotic, anti-inflammatory, and antioxidative properties against the α-syn- and MPTP-generated humanized in vitro PD-like pathology. This study determined that the cytoprotective effects of M3G are mediated by nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase (HO)-1 signaling. Full article

(This article belongs to the Special Issue Programmed Cell Death and Oxidative Stress: 3rd Edition)

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Review

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14 pages, 695 KB

Open AccessReview

Targeting Survivin: Now I Become Death, the Destroyer of Cells

by Mia Fanuzzi, Shuhua Zheng, Craig M. Horbinski, Maryam A. Shaaban, Harrshavasan Congivaram, Ruochen Du, Shashwat Tripathi, Lisa Hurley, Priya Kumthekar, Atique Ahmed, Daniel J. Brat, Maciej S. Lesniak and Amy B. Heimberger

Int. J. Mol. Sci. 2025, 26(23), 11417; https://doi.org/10.3390/ijms262311417 - 26 Nov 2025

Viewed by 345

Abstract

Survivin (BIRC5) plays a key role in inhibiting apoptosis and is highly expressed in many cancers, including gliomas and breast cancer, where it contributes to tumor progression, therapeutic resistance and poor patient outcomes. With a dual function in promoting cell proliferation and survival, coupled with its potential immunogenicity, survivin is a compelling therapeutic target for cancer; yet, it has no FDA-approved agents to date. Here, we review key findings from preclinical models that emphasize how survivin contributes to chemoresistance and radioresistance; summarize the clinical landscape of survivin-targeted strategies, highlighting both the successes and limitations of these approaches; and outline next steps to optimize survivin-targeted therapies, including the need to integrate biomarker-focused patient selection and the potential for combination therapies. These insights establish survivin as a key driver of cancer progression and a promising target for future therapeutic development. Full article

(This article belongs to the Special Issue Programmed Cell Death and Oxidative Stress: 3rd Edition)

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18 pages, 1306 KB

Open AccessReview

Trigger Points of Necroptosis (RIPK1, RIPK3, and MLKL)—Promising Horizon or Blind Alley in Therapy of Colorectal Cancer?

by Marcin Sokołowski and Aleksandra Butrym

Int. J. Mol. Sci. 2025, 26(22), 11101; https://doi.org/10.3390/ijms262211101 - 17 Nov 2025

Viewed by 1005

Abstract

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, due to the limited efficacy of current therapeutic strategies in advanced stages. Necroptosis, a regulated form of necrotic cell death mediated by receptor-interacting protein kinases RIPK1 and RIPK3, and the pseudokinase MLKL, has emerged as a potential alternative pathway to induce cancer cell death. Recent studies suggest that modulation of necroptosis may enhance antitumor immunity, overcome therapeutic resistance, and improve clinical outcomes in CRC. In this review, we systematically analyzed the current literature on the role of necroptosis in CRC, focusing on molecular mechanisms, experimental models, and therapeutic implications. By critically evaluating the available evidence, we aimed to determine whether targeting RIPK1, RIPK3, and MLKL, or other novel agents, represents a promising horizon or a blind alley in the development of novel CRC therapies. Full article

(This article belongs to the Special Issue Programmed Cell Death and Oxidative Stress: 3rd Edition)

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20 pages, 777 KB

Open AccessReview

Immune Checkpoint Inhibitors (ICI) in Urological Cancers: A New Modern Era, but Not Generally Applied

by Marcin Sokołowski, Anna Sokołowska, Magdalena Chrząszcz and Aleksandra Butrym

Int. J. Mol. Sci. 2025, 26(15), 7194; https://doi.org/10.3390/ijms26157194 - 25 Jul 2025

Cited by 1 | Viewed by 1500 | Correction

Abstract

The modern era of systemic treatment of urological cancers is definitely marked by checkpoint inhibitors. Over the past 30 years, checkpoint inhibitors have changed the oncological world, especially in chemoresistant malignancies. Multiple investigations focused on immunotherapy in urological cancers have carved new paradigms and changed clinical guidelines. However, some clinical trials have been blind alleys for systemic therapy. After a scrutinized review of electronic databases, we want to present the natural history and courses of clinical trials in urological malignancies. All of them contribute to expanding the knowledge and experience of clinicians, and some of them improve the prognosis and prolong the overall survival of oncological patients. In conclusion, checkpoint inhibitors open a new modern era in some urological cancers, but not overall. Future perspectives are focused on combination with targeted therapy and could be a new way forward in the systemic treatment of urological cancers. Full article

(This article belongs to the Special Issue Programmed Cell Death and Oxidative Stress: 3rd Edition)

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