Dongming Wu

Radiation-induced skin injury (RISI) is a common and refractory complication during tumor radiotherapy, characterized by radiation stress-induced impairmen

Pyroptosis, particularly gasdermin E (GSDME)-mediated programmed cell death, has emerged as a crucial determinant of chemosensitivity and antitumor immunit

Introduction: Acute lung injury (ALI) is a critical condition with diverse etiologies, characterized by high mortality rates and a lack of specific therapeutic interventions. Farrerol, a naturally occurring flavonoid isolated from Rhododendron spp., exhibits potent anti-inflammatory and antioxidant activities. Previous studies have indicated that farrerol exerts protective effects against lipopolysaccharide (LPS)-induced ALI; however, the underlying mechanisms remain elusive. This study aimed to elucidate the protective mechanisms of farrerol against LPS-induced ALI. Methods: We evaluated the efficacy of farrerol using both in vitro (LPS-stimulated BEAS-2B cells) and in vivo (LPS-induced ALI in mice) models. The protective mechanism of rhododendron against ALI was investigated using proteomics, cellular thermal shift assays, co-immunoprecipitation, and molecular docking. Results: Pretreatment with farrerol significantly improved cell viability and reduced lactate dehydrogenase release in LPS-induced BEAS-2B cells. In vivo , farrerol effectively alleviated LPS−induced pulmonary edema and histopathological damage in mice. Mechanistically, we found that farrerol directly binds to and stabilizes runt-related transcription factor 1 (RUNX1), thereby transcriptionally activating the expression of solute carrier family 7 member 11. Overexpression of RUNX1 mimicked the protective effects of farrerol, while knockdown of RUNX1 abolished these effects. Discussion: Farrerol could directly bind and stabilize the expression of RUNX1, thereby enhancing SLC7A11 transcription and ultimately inhibiting ferroptosis. Thus, farrerol is a potential therapeutic agent for ALI.

Lung cancer is a common malignant neoplasm, one of the leading causes of death worldwide. Cancer stem cells (CSCs) drive tumor recurrence, progression, and therapeutic resistance. Thus, targeting CSCs may contribute to lung cancer treatment and improve clinical outcomes. We induced stem cell formation in serum-free suspension culture. Cell viability was assessed using the cell counting-kit 8 assay, and cell membrane integrity was evaluated using the lactate dehydrogenase release assay. Caspase-1 activity assays, western blotting, enzyme-linked immunosorbent assay, and flow cytometry were used to analyze pyroptosis in cells. Confocal microscopy was used to detect protein co-localization. Quantification of fluorescence intensity and co-localization was carried out using ImageJ software. Co-immunoprecipitation was performed to assess the interaction between GOLPH3 and MYO18A. An animal study was conducted to evaluate the effects of golgicide A (GCA) on tumor growth in vivo. GCA induced cell death via pyroptosis in both H1650- and A549-derived CSCs. GCA enhanced the binding of GOLPH3 and MYO18A, resulting in trans-Golgi network (TGN) dispersion. In turn, the dispersed TGN (dTGN) recruited NLRP3. Our xenograft animal model study confirmed that GCA can inhibit tumor growth. GCA induced pyroptosis by promoting the interaction between GOLPH3 and MYO18A, resulting in dTGN formation in lung CSCs. Our findings provide a novel molecular insight into the anti-cancer activities of GCA in lung CSCs.

Radiation-induced lung injury (RILI) is the most common complication experienced by patients with thoracic tumors after radiotherapy. Among patients receiving thoracic tumor radiotherapy, 14.6–37.2% develop RILI. RILI is characterized by an acute inflammatory response; however, the exact mechanism remains unclear and an ideal drug is still lacking. In this study, we investigated the protective effects of flagellin A with linked C- and N-terminal ends (FlaA N/C) against the development of RILI. Mice and bronchial epithelial cells were exposed to radiation (15 Gy) after FlaA N/C treatment. Lung injury, bronchial epithelial cell injury, and RILI were assessed by histological evaluation in vivo and cell viability and cell death detection in vitro. Pyroptosis was assessed by western blotting (WB), immunofluorescence (IF), and immunohistochemistry (IHC). To explore the molecular mechanisms by which FlaA N/C inhibits RILI, conditional Beclin 1 (Beclin1+/−) and NLR family CARD domain-containing protein 4 (Nlrc4)-knockout (Nlrc4−/−) mice were generated. An autophagy inhibitor was used for in vitro cell assays, and pyroptosis indicators were detected. Data were analyzed using one-way analysis of variance. FlaA N/C attenuated radiation-induced lung tissue damage, pro-inflammatory cytokine release, and pyroptosis in vivo and cell viability, cell death, and pyroptosis in vitro. Mechanistically, FlaA N/C activated the neuronal apoptosis inhibitory protein (NAIP)/NLRC4/apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) inflammasome, which was then degraded during Beclin 1-mediated autophagy. Deletion of the FlaA N/C D0 domain reversed the inhibitory effect of FlaA N/C on radiation-induced pyroptosis in vivo and in vitro. Similarly, Nlrc4-knockout in vivo or inhibition of autophagy in vitro eliminated the protective effects of FlaA N/C against radiation-induced pyroptosis. These results indicate that FlaA N/C attenuates RILI by promoting NAIP/NLRC4/ASC inflammasome autophagy and inhibiting pyroptosis. This study provides a potential approach for RILI intervention.