MAPK8 and obesity due to melanocortin 4 receptor deficiency: Obesity or T2DM leads to increased secretion of the pro-inflammatory factor TNF-α, thereby activating kinases such as JNK and IKK. Subsequent inhibition of HSF1 results in downregulation of iHSP72, exacerbating insulin resistance and disrupting protein homeostasis. Hyperglycaemia or oxidative stress prompts immune cells to release eHSP72, thereby intensifying inflammation.