Acid-sensing ion channel 1 (ASIC1) is a proton-gated cation channel. It is related to degenerin channels (DEGs), epithelial sodium cation channels (ENaCs), and FMRF-amide (Phe-Met-Arg-Phe-NH2)-gated channels (FaNaC). Its activation physiologically leads to pain perception, synaptic plasticity, learning and memory, fear, ischemic neuronal injury, seizure termination, neuronal degeneration, and mechanosensation. It detects extracellular acid fluctuation and responds to acidic pH by increasing membrane depolarization rate, conducting cations like Na+ and Ca2+ across the membrane upon protonation [6].

In atherosclerosis, ASIC1 protein levels are increased in CD68+ macrophages in human aortic lesions and AopE-/- mouse lesion areas. ASIC1 interacts with RIP1, promoting RIP1 phosphorylation at serine 166 and TFEB phosphorylation at serine 142, disrupting lipophagy and increasing lipid accumulation. Silencing ASIC1 expression or inhibiting RIP1 activation in ApoE-/- mouse models attenuates atherogenesis and restores TFEB-mediated lipophagy [1].

In hepatocellular carcinoma (HCC), ASIC1 is upregulated in HCC tissues. In vivo and in vitro experiments show that ASIC1 enhances the migration and invasion capabilities of HCC cells by activating the PRKACA/AP-1 signaling pathway [2].

In pancreatic cancer, pancreatic cancer cells induce ASIC1 overexpression in pancreatic stellate cells (PSCs). Inhibiting ASIC1 weakens the enhanced proliferation and migration of PSCs induced by pancreatic cancer cells, and ASIC1 participates in this regulation via the ERK pathway [3].

In the formalin acute pain mouse model, formalin injection increases ASIC1 levels at the contralateral anterior cingulate cortex and in a gradient at the spinal cord and dorsal root ganglia [4].

In adult offspring rats with prenatal maternal stress, spinal ASIC1 protein expression and synaptic transmission are enhanced, and miR-485 may mediate enterodynia through ASIC1 [5].

In chronic hypoxia-induced pulmonary hypertension, ASIC1 knockout (ASIC1-/-) mice show blunted acute hypoxic pulmonary vasoconstriction (HPV) responses, diminished right ventricular systolic pressure, right ventricular hypertrophy, and arterial remodeling compared with wild-type mice. ASIC1 also contributes to CH-and endothelin-1-induced Ca2+ responses and NFATc3 nuclear import in pulmonary arterial smooth muscle cells in a PICK1-dependent manner [7,8].

In conclusion, ASIC1 plays a crucial role in multiple biological processes and diseases. Gene knockout mouse models, especially ASIC1-/- mice, have been instrumental in revealing its functions in atherosclerosis, HCC, pancreatic cancer, pain, and pulmonary hypertension. These findings enhance our understanding of the underlying mechanisms of these diseases and suggest ASIC1 as a potential therapeutic target.