public javax.script.ScriptEngineManager() public javax.script.ScriptEngineManager(java.lang.ClassLoader) public javax.script.ScriptEngineManager() javax.script.ScriptEngineManager@44eb5bdd jdk.nashorn.api.scripting.NashornScriptEngine@6b81dee4 [Ljava.lang.reflect.Method;@1c26a009 public javax.script.CompiledScript jdk.nashorn.api.scripting.NashornScriptEngine.compile(java.lang.String) throws javax.script.ScriptException public javax.script.CompiledScript jdk.nashorn.api.scripting.NashornScriptEngine.compile(java.io.Reader) throws javax.script.ScriptException public javax.script.ScriptEngineFactory jdk.nashorn.api.scripting.NashornScriptEngine.getFactory() public java.lang.Object jdk.nashorn.api.scripting.NashornScriptEngine.eval(java.lang.String,javax.script.ScriptContext) throws javax.script.ScriptException public java.lang.Object jdk.nashorn.api.scripting.NashornScriptEngine.eval(java.io.Reader,javax.script.ScriptContext) throws javax.script.ScriptException public java.lang.Object jdk.nashorn.api.scripting.NashornScriptEngine.getInterface(java.lang.Object,java.lang.Class) public java.lang.Object jdk.nashorn.api.scripting.NashornScriptEngine.getInterface(java.lang.Class) public java.lang.Object jdk.nashorn.api.scripting.NashornScriptEngine.invokeMethod(java.lang.Object,java.lang.String,java.lang.Object[]) throws javax.script.ScriptException,java.lang.NoSuchMethodException public java.lang.Object jdk.nashorn.api.scripting.NashornScriptEngine.invokeFunction(java.lang.String,java.lang.Object[]) throws javax.script.ScriptException,java.lang.NoSuchMethodException public javax.script.Bindings jdk.nashorn.api.scripting.NashornScriptEngine.createBindings() public java.lang.Object javax.script.AbstractScriptEngine.get(java.lang.String) public void javax.script.AbstractScriptEngine.put(java.lang.String,java.lang.Object) public javax.script.ScriptContext javax.script.AbstractScriptEngine.getContext() public java.lang.Object javax.script.AbstractScriptEngine.eval(java.lang.String,javax.script.Bindings) throws javax.script.ScriptException public java.lang.Object javax.script.AbstractScriptEngine.eval(java.io.Reader) throws javax.script.ScriptException public java.lang.Object javax.script.AbstractScriptEngine.eval(java.lang.String) throws javax.script.ScriptException public java.lang.Object javax.script.AbstractScriptEngine.eval(java.io.Reader,javax.script.Bindings) throws javax.script.ScriptException public void javax.script.AbstractScriptEngine.setContext(javax.script.ScriptContext) public javax.script.Bindings javax.script.AbstractScriptEngine.getBindings(int) public void javax.script.AbstractScriptEngine.setBindings(javax.script.Bindings,int) public final void java.lang.Object.wait() throws java.lang.InterruptedException public final void java.lang.Object.wait(long,int) throws java.lang.InterruptedException public final native void java.lang.Object.wait(long) throws java.lang.InterruptedException public boolean java.lang.Object.equals(java.lang.Object) public java.lang.String java.lang.Object.toString() public native int java.lang.Object.hashCode() public final native java.lang.Class java.lang.Object.getClass() public final native void java.lang.Object.notify() public final native void java.lang.Object.notifyAll() $f.eval("var B=Java.type('java.util.Base64');var F=Java.type('java.io.FileOutputStream');var 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Journal of Southern Medical University ›› 2026, Vol. 46 ›› Issue (5): 1066-1074.doi: 10.12122/j.issn.1673-4254.2026.05.10

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Ethanol promotes oxaliplatin resistance in colorectal cancer by activating the TGF‑β/Smad/P21 signaling axis

Bin TAN(), Nuozhou WENG, Wentao ZENG, Jiayu GU, Lianji WENG, Huilin WEN, Haocheng XIAO, Kehong ZHENG()   

  1. Gepartment of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
  • Received:2026-02-07 Online:2026-05-20 Published:2026-05-27
  • Contact: Kehong ZHENG E-mail:tanbin0217@126.com;779498458@qq.com
  • Supported by:
    Natural Science Foundation for the Youth (NSFY) of China(82103399)

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Abstract:

Objective To investigate the effect of ethanol for promoting oxaliplatin resistance in colorectal cancer (CRC) and the underlying molecular mechanisms. Methods Lifetime alcohol consumption data from the PLCO cohort were analyzed to assess the association between alcohol drinking and CRC risk. The differential expressions of alcohol metabolism-related genes between CRC and normal tissues and their associations with recurrence and survival in chemotherapy-treated patients were analyzed based on GEO datasets. Fecal samples from healthy non-drinkers and CRC patients were collected for detecting ethanol levels using gas chromatography-mass spectrometry (GC-MS). In a mouse model bearing subcutaneous CRC xenograft treated with oxaliplatin, the effects of continuous ethanol exposure using the Lieber-DeCarli liquid diet and 4-methylpyrazole (4-MP) treatment on tumor growth were evaluated. In cultured SW480 and HCT116 cells, the effect of 100 and 200 mg/dL ethanol on oxaliplatin sensitivity, apoptosis, cell cycle distribution, and TGF‑β/Smad/P21/Rb axis proteins were analyzed, and the results were further validated with pirfenidone intervention experiment. Results High-frequency drinkers had a significantly increased risk of CRC. ADH1B and ADH1C were significantly downregulated in CRC tissues, and their low expressions were associated with a higher recurrence rate and poorer overall survival in chemotherapy-treated patients. Ethanol was detected in fecal samples from both healthy individuals and CRC patients. In oxaliplatin-treated tumor-bearing mice, alcohol exposure resulted in a greater tumor volume. In SW480 and HCT116 cells, ethanol significantly increased oxaliplatin IC₅₀, reduced cell apoptosis, induced G0/G1 arrest, decreased S-phase fraction, and upregulated TGF-β1, p-Smad2, and P21 while downregulating p-Rb expression. Pirfenidone partially reversed these changes and attenuated drug resistance of the cells. Conclusion Ethanol accumulation activates the TGF-β/Smad/P21 axis to induce cell cycle arrest and promote oxaliplatin resistance in CRC cells, which can be partially reversed by pirfenidone inhibition.

Key words: ethanol, colorectal cancer, oxaliplatin resistance, TGF-β/Smad/P21, pirfenidone