Objectives We have shown that 4‐HNE induces signaling for apoptosis in cells via death receptor (Fas) mediated extrinsic and p53‐mediated intrinsic pathways. However, the nature of interactions of 4‐HNE with the components of these signaling pathways are not understood. During present studies, we have elucidated the pathways of 4‐HNE induced signaling for apoptosis in HepG2 cells. Results Our results showed that 4‐HNE promoted apoptosis in HepG2 cells through activation of p53, Bax, p21, JNK, and caspase3. Our results also showed that exposure of HepG2 cells to 4‐HNE leads to the activation of Fas, Daxx, ASK1, JNK, and caspase3 and these effects of 4‐HNE could be inhibited by the over expression of hGSTA4‐4. 4‐HNE also induced translocation of Daxx from nucleus to cytoplasm which caused inhibition of apoptosis and the activation and the translocation of HSF1 to nucleus resulting in the up‐regulation of HSP70. We also demonstrate that 4‐HNE does indeed bind to Fas, Daxx, and p53 to affect Fas and p53 mediated signaling. Conclusion These findings suggest that 4‐HNE generated during oxidative stress promotes apoptosis through multiple pathways, but upon sustained oxidative stress conditions, 4‐HNE may provide protection to cells by up regulation of heat shock proteins and by Daxx mediated inhibition of apoptosis.( NIH grants ES 012171, EY04396 (YCA) and CA 077495 (SA))