Heteronemin (Haimian jing) is a sesterterpenoid-type natural marine product that is isolated from sponges and has anticancer properties. It inhibits cancer cell proliferation via different mechanisms, such as reactive oxygen species (ROS) production, cell cycle arrest, apoptosis as well as proliferative gene changes in various types of cancers. Recently, the novel structure and bioactivity evaluation of heteronemin has received extensive attention. Hormones control physiological activities regularly, however, they may also affect several abnormalities such as cancer. L-Thyroxine (T4), steroid hormones, and epidermal growth factor (EGF) up-regulate the accumulation of checkpoint programmed death-ligand 1 (PD-L1) and promote inflammation in cancer cells. Heteronemin suppresses PD-L1 expression and reduces the PD-L1-induced proliferative effect. In the current review, we evaluated research and evidence regarding the antitumor effects of heteronemin and the antagonizing effects of non-peptide hormones and growth factors on heteronemin-induced anti-cancer properties and utilized computational molecular modeling to explain how these ligands interacted with the integrin αvβ3 receptors. On the other hand, thyroid hormone deaminated analogue, tetraiodothyroacetic acid (tetrac), modulates signal pathways and inhibits cancer growth and metastasis. The combination of heteronemin and tetrac derivatives has been demonstrated to compensate for anti-proliferation in cancer cells under different circumstances. Overall, this review outlines the potential of heteronemin in managing different types of cancers that may lead to its clinical development as an anticancer agent.
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