Clobetasol propionate, a Nrf-2 inhibitor, sensitizes human lung cancer cells to radiation-induced killing via mitochondrial ROS-dependent ferroptosis

Archita Rai1,2, Raghavendra S. Patwardhan1, Sundarraj Jayakumar1,2, Pradnya Pachpatil2,3, Dhruv Das2,4, Girish Ch. Panigrahi5, Vikram Gota5, Sejal Patwardhan2,5, Santosh K. Sandur1,2
1 Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India
2 Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai 400094, India
3 Bio Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India
4 Applied Genomics Section, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India
5 Advanced Centre for Treatment Research & Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai 410210, India
Correspondence to: Santosh K. Sandur:,
DOI: 10.1038/s41401-024-01233-8
Received: 21 June 2023
Accepted: 24 January 2024
Advance online: 13 March 2024


Combining radiotherapy with Nrf-2 inhibitor holds promise as a potential therapeutic strategy for radioresistant lung cancer. Here, the radiosensitizing efficacy of a synthetic glucocorticoid clobetasol propionate (CP) in A549 human lung cancer cells was evaluated. CP exhibited potent radiosensitization in lung cancer cells via inhibition of Nrf-2 pathway, leading to elevation of oxidative stress. Transcriptomic studies revealed significant modulation of pathways related to ferroptosis, fatty acid and glutathione metabolism. Consistent with these findings, CP treatment followed by radiation exposure showed characteristic features of ferroptosis in terms of mitochondrial swelling, rupture and loss of cristae. Ferroptosis is a form of regulated cell death triggered by iron-dependent ROS accumulation and lipid peroxidation. In combination with radiation, CP showed enhanced iron release, mitochondrial ROS, and lipid peroxidation, indicating ferroptosis induction. Further, iron chelation, inhibition of lipid peroxidation or scavenging mitochondrial ROS prevented CP-mediated radiosensitization. Nrf-2 negatively regulates ferroptosis through upregulation of antioxidant defense and iron homeostasis. Interestingly, Nrf-2 overexpressing A549 cells were refractory to CP-mediated ferroptosis induction and radiosensitization. Thus, this study identified anti-psoriatic drug clobetasol propionate can be repurposed as a promising radiosensitizer for Keap-1 mutant lung cancers.
Keywords: clobetasol propionate; radiosensitization; iron homeostasis; lipid peroxidation; non-small cell lung carcinoma; glucocorticoid

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