{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n DNA damage‐induced apoptosis suppressor (DDIAS), also known as hNoxin, is a stress‐responsive, anti‐apoptotic protein that promotes the survival and malignant behavior of cancer cells. DDIAS is transcriptionally upregulated in response to DNA damage and various growth signals. For example, its expression is activated by the transcription factor NFATc1 and also through growth factor–stimulated ERK5/MEF2B signaling following epidermal growth factor exposure, events that collectively contribute to cisplatin resistance and enhanced invasive potential via increased β‐catenin signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, DDIAS protects cancer cells from apoptotic stimuli. In lung and hepatocellular carcinoma cells, DDIAS interferes with death receptor–mediated apoptosis by binding to the death effector domain of FADD—thus blocking the assembly of the death-inducing signaling complex—and by stabilizing caspase-8 through inhibition of its ubiquitination, thereby preventing its degradation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Furthermore, by impeding the interaction between STAT3 and its phosphatase (PTPRM), DDIAS maintains the tyrosine phosphorylation and activation of STAT3, which in turn supports oncogenic transcriptional programs that promote tumor cell proliferation and survival"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "; this mechanism is further underscored by studies showing that pharmacological inhibitors of DDIAS transcription or of the DDIAS/STAT3 interaction reduce STAT3 activity and tumor growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n The anti-apoptotic and pro-survival properties of DDIAS are complemented by mechanisms regulating its stability. For instance, DDIAS is targeted for proteasomal degradation by the CHIP/HSP70 complex, and alterations in this degradation pathway can contribute to its accumulation in cancer cells, thereby reinforcing chemoresistance and invasive behavior."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, studies using stress models have demonstrated that DDIAS/hNoxin is induced by a variety of DNA-damaging conditions, and its knockdown sensitizes cancer cells to apoptosis, emphasizing its potential as a therapeutic target in lung, pancreatic, and other cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings indicate that DDIAS functions as a multifaceted oncogenic factor by inhibiting apoptosis through interference with death receptor signaling and caspase-8 turnover, by sustaining STAT3-mediated transcriptional programs, and by promoting tumor cell invasion via β-catenin activation. Owing to its central role in promoting cell survival and therapeutic resistance, DDIAS represents a promising candidate for targeted anticancer strategies.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Joo-Young Im, Kang-Woo Lee, Kyoung-Jae Won, et al. 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