Caspase-independent cell death in lung cancer: from mechanisms to clinical applications

Gupta, G; Samuel, VP; M., RM; Rani, B; Sasikumar, Y; Nayak, PP; Sudan, P; Goyal, K; Oliver, BG; Chakraborty, A; Dua, K

Caspase-independent cell death in lung cancer: from mechanisms to clinical applications

Gupta, G Samuel, VP M., RM Rani, B Sasikumar, Y Nayak, PP Sudan, P Goyal, K Oliver, BG Chakraborty, A Dua, K

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Publisher:: Springer Science and Business Media LLC
Publication Type:: Journal Article
Citation:: Naunyn-Schmiedeberg's Archives of Pharmacology

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Field	Value	Language
dc.contributor.author	Gupta, G
dc.contributor.author	Samuel, VP
dc.contributor.author	M., RM
dc.contributor.author	Rani, B
dc.contributor.author	Sasikumar, Y
dc.contributor.author	Nayak, PP
dc.contributor.author	Sudan, P
dc.contributor.author	Goyal, K
dc.contributor.author	Oliver, BG
dc.contributor.author	Chakraborty, A
dc.contributor.author	Dua, K https://orcid.org/0000-0002-7507-1159
dc.date.accessioned	2025-04-22T14:14:39Z
dc.date.available	2025-04-22T14:14:39Z
dc.identifier.citation	Naunyn-Schmiedeberg's Archives of Pharmacology
dc.identifier.issn	0028-1298
dc.identifier.issn	1432-1912
dc.identifier.uri	http://hdl.handle.net/10453/186955
dc.description.abstract	<jats:title>Abstract</jats:title> <jats:p>Caspase-independent cell death (CICD) has recently become a very important mechanism in lung cancer, in particular, to overcome a critical failure in apoptotic cell death that is common to disease progression and treatment failures. The pathways involved in CICD span from necroptosis, ferroptosis, mitochondrial dysfunction, and autophagy-mediated cell death. Its potential therapeutic applications have been recently highlighted. Glutathione peroxidase 4 (GPX4) inhibition-driven ferroptosis has overcome drug resistance in non-small cell lung cancer (NSCLC). In addition, necroptosis involving RIPK1 and RIPK3 causes tumor cell death and modulation of immune responses in the tumor microenvironment (TME). Mitochondrial pathways are critical for CICD through modulation of metabolic and redox homeostasis. Ferroptosis is amplified by mitochondrial reactive oxygen species (ROS) and lipid peroxidation in lung cancer cells, and mitochondrial depolarization induces oxidative stress and leads to cell death. In addition, mitochondria-mediated autophagy, or mitophagy, results in the clearance of damaged organelles under stress conditions, while this function is also linked to CICD when dysregulated. The role of cell death through autophagy regulated by ATG proteins and PI3K/AKT/mTOR pathway is dual: to suppress tumor and to sensitize cells to therapy. A promising approach to enhancing therapeutic outcomes involves targeting mechanisms of CICD, including inducing ferroptosis by SLC7A11 inhibition, modulating mitochondrial ROS generation, or combining inhibition of autophagy with chemotherapy. Here, we review the molecular underpinnings of CICD, particularly on mitochondrial pathways and their potential to transform lung cancer treatment.</jats:p>
dc.language	en
dc.publisher	Springer Science and Business Media LLC
dc.relation.ispartof	Naunyn-Schmiedeberg's Archives of Pharmacology
dc.relation.isbasedon	10.1007/s00210-025-04149-0
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1115 Pharmacology and Pharmaceutical Sciences, 1116 Medical Physiology
dc.subject.classification	Pharmacology & Pharmacy
dc.subject.classification	3214 Pharmacology and pharmaceutical sciences
dc.title	Caspase-independent cell death in lung cancer: from mechanisms to clinical applications
dc.type	Journal Article
utslib.for	1115 Pharmacology and Pharmaceutical Sciences
utslib.for	1116 Medical Physiology
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Health
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/Centre for Inflammation (CFI)
pubs.organisational-group	University of Technology Sydney/UTS Groups/Centre for Inflammation (CFI)/Centre for Inflammation (CFI) Associate Members
pubs.organisational-group	University of Technology Sydney/UTS Groups/Australian Research Consortium in Complementary and Integrative Medicine (ARCCIM)
pubs.organisational-group	University of Technology Sydney/UTS Groups/Stroke Research Collaborative
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2025-04-22T14:14:38Z
pubs.publication-status	Published online

Abstract:

Abstract Caspase-independent cell death (CICD) has recently become a very important mechanism in lung cancer, in particular, to overcome a critical failure in apoptotic cell death that is common to disease progression and treatment failures. The pathways involved in CICD span from necroptosis, ferroptosis, mitochondrial dysfunction, and autophagy-mediated cell death. Its potential therapeutic applications have been recently highlighted. Glutathione peroxidase 4 (GPX4) inhibition-driven ferroptosis has overcome drug resistance in non-small cell lung cancer (NSCLC). In addition, necroptosis involving RIPK1 and RIPK3 causes tumor cell death and modulation of immune responses in the tumor microenvironment (TME). Mitochondrial pathways are critical for CICD through modulation of metabolic and redox homeostasis. Ferroptosis is amplified by mitochondrial reactive oxygen species (ROS) and lipid peroxidation in lung cancer cells, and mitochondrial depolarization induces oxidative stress and leads to cell death. In addition, mitochondria-mediated autophagy, or mitophagy, results in the clearance of damaged organelles under stress conditions, while this function is also linked to CICD when dysregulated. The role of cell death through autophagy regulated by ATG proteins and PI3K/AKT/mTOR pathway is dual: to suppress tumor and to sensitize cells to therapy. A promising approach to enhancing therapeutic outcomes involves targeting mechanisms of CICD, including inducing ferroptosis by SLC7A11 inhibition, modulating mitochondrial ROS generation, or combining inhibition of autophagy with chemotherapy. Here, we review the molecular underpinnings of CICD, particularly on mitochondrial pathways and their potential to transform lung cancer treatment.

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http://hdl.handle.net/10453/186955