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Background <p>Excess palmitate (PA) induces lipid accumulation, and oxidative stress in hepatocytes, contributing to metastasis and multidrug resistance in hepatocellular carcinoma (HCC). Oleate (OA) attenuates PA-induced lipotoxicity. This study examines how PA, OA, and their combination modulate oxidative stress, NRF2 signaling, and regulators of metastasis (MMP9) and multidrug resistance (MRP1) in HepG2 cells.</p> Methods <p>HepG2 cells were treated for 24&#xa0;h with IC₅₀ concentrations of PA (0.8&#xa0;μM), OA (1.0&#xa0;μM), or PA/OA (0.6:0.9&#xa0;μM), determined by MTT assay. Lipid droplets were quantified by Oil Red O staining. Reactive oxygen species (ROS) and malondialdehyde (MDA) levels were measured spectrophotometrically. Gene expression of <i>NRF2</i>, <i>MRP1</i>, and <i>MMP9</i> was assessed by RT-qPCR.</p> Results <p>PA and OA induced comparable lipid droplet accumulation (P &gt; 0.05), whereas PA/OA synergistically enhanced steatosis (P &lt; 0.0001 vs. control). PA significantly increased ROS (P &lt; 0.01) and showed a tendency to elevate MDA (P = 0.07), while PA/OA normalized ROS to control levels (P &gt; 0.05 vs. control) and reduced MDA (P &lt; 0.05). PA/OA robustly upregulated <i>NRF2</i> (~ 5.2-fold; P &lt; 0.01) and <i>MRP1</i> (~ 5.3-fold; P &lt; 0.0001), with significant differences vs. PA and OA alone. <i>MMP9</i> expression remained unchanged across all treatments (P &gt; 0.05).</p> Conclusion <p>Co-administration of OA counteracts PA-induced oxidative stress and lipotoxicity despite enhancing steatosis, mediated by pronounced NRF2 pathway activation and <i>MRP1</i> upregulation. This adaptive cytoprotective response may promote tumor cell survival and multidrug resistance in HCC, highlighting the context-dependent role of dietary fatty acid composition in hepatocarcinogenesis and therapeutic vulnerability.</p>

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Palmitate and oleate differentially regulate oxidative stress and drug resistance markers in steatotic HepG2 cells

  • 期刊论文

  • 发表日期：

    2026年4月27日

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  • Sajedeh Sabzian,
  • Yaser Mohammadi,
  • Samaneh Torabi,
  • Elham Bahreini

摘要

Background

Excess palmitate (PA) induces lipid accumulation, and oxidative stress in hepatocytes, contributing to metastasis and multidrug resistance in hepatocellular carcinoma (HCC). Oleate (OA) attenuates PA-induced lipotoxicity. This study examines how PA, OA, and their combination modulate oxidative stress, NRF2 signaling, and regulators of metastasis (MMP9) and multidrug resistance (MRP1) in HepG2 cells.

Methods

HepG2 cells were treated for 24 h with IC₅₀ concentrations of PA (0.8 μM), OA (1.0 μM), or PA/OA (0.6:0.9 μM), determined by MTT assay. Lipid droplets were quantified by Oil Red O staining. Reactive oxygen species (ROS) and malondialdehyde (MDA) levels were measured spectrophotometrically. Gene expression of NRF2, MRP1, and MMP9 was assessed by RT-qPCR.

Results

PA and OA induced comparable lipid droplet accumulation (P > 0.05), whereas PA/OA synergistically enhanced steatosis (P < 0.0001 vs. control). PA significantly increased ROS (P < 0.01) and showed a tendency to elevate MDA (P = 0.07), while PA/OA normalized ROS to control levels (P > 0.05 vs. control) and reduced MDA (P < 0.05). PA/OA robustly upregulated NRF2 (~ 5.2-fold; P < 0.01) and MRP1 (~ 5.3-fold; P < 0.0001), with significant differences vs. PA and OA alone. MMP9 expression remained unchanged across all treatments (P > 0.05).

Conclusion

Co-administration of OA counteracts PA-induced oxidative stress and lipotoxicity despite enhancing steatosis, mediated by pronounced NRF2 pathway activation and MRP1 upregulation. This adaptive cytoprotective response may promote tumor cell survival and multidrug resistance in HCC, highlighting the context-dependent role of dietary fatty acid composition in hepatocarcinogenesis and therapeutic vulnerability.