tetano
Editor, Senior Moderator
Biochem Pharmacol
. 2026 Aug 6:118321.
doi: 10.1016/j.bcp.2026.118321. Online ahead of print.
The L-type calcium channel Ca[SUB]v[/SUB]1.2 mediates influenza A virus infection by regulating viral internalization and endoplasmic reticulum homeostasis
Zhixuan Chen[SUP] 1 [/SUP], Ran Luo[SUP] 1 [/SUP], Siqi Luo[SUP] 1 [/SUP], Hanhui Zhong[SUP] 1 [/SUP], Xucheng He[SUP] 1 [/SUP], Yinyan Li[SUP] 1 [/SUP], Jinxiang Chen[SUP] 1 [/SUP], Jie Yang[SUP] 2 [/SUP]
Affiliations
Influenza A virus (IAV) remains a major global health threat due to its high mutation rate and the emergence of antiviral resistance. Targeting host factors provides an alternative therapeutic strategy to overcome these challenges. Previous studies have shown that the L-type calcium channel Ca[SUB]v[/SUB]1.2 was implicated in viral infections. In this study, we aimed to clarify the mechanism by which Ca[SUB]v[/SUB]1.2 acts as a critical host factor mediating IAV infection, using the dihydropyridine-type calcium channel blocker nisoldipine. Nisoldipine showed notable antiviral activity in both in vitro and in vivo models. Mechanistically, nisoldipine inhibited IAV internalization by targeting Ca[SUB]v[/SUB]1.2, thereby suppressing calcium-dependent activation of the Ras-PI3K-AKT, RhoA-ROCK, and JNK pathways associated with viral internalization. Moreover, nisoldipine modulated the unfolded protein response (UPR) in host cells by promoting adaptive XBP1 splicing and contributed to the maintenance of endoplasmic reticulum (ER) homeostasis during IAV infection. Collectively, these observations support a sequential cascade model: Ca[SUB]v[/SUB]1.2 inhibition restrains viral entry and indirectly mitigates virus-triggered ER stress. Furthermore, nisoldipine exhibits broad-spectrum in vitro antiviral activity against multiple enveloped RNA and DNA viruses, including human coronavirus OC43 (HCoV-OC43), respiratory syncytial virus (RSV), Zika virus (ZIKV), Dengue virus Type 2 (DENV2), and Herpes Simplex Virus Type 1/2 (HSV-1/2). This study clarifies the mechanistic involvement of Ca[SUB]v[/SUB]1.2 in IAV infection and further identifies it as a promising broad-spectrum antiviral target with potential applications in preventing and treating influenza, human coronavirus infections, and other emerging viral diseases.
Keywords: Broad-spectrum antiviral activity; Host-targeted therapy; Influenza A virus; Internalization; L-type calcium channel Ca(v)1.2; Nisoldipine.
. 2026 Aug 6:118321.
doi: 10.1016/j.bcp.2026.118321. Online ahead of print.
The L-type calcium channel Ca[SUB]v[/SUB]1.2 mediates influenza A virus infection by regulating viral internalization and endoplasmic reticulum homeostasis
Zhixuan Chen[SUP] 1 [/SUP], Ran Luo[SUP] 1 [/SUP], Siqi Luo[SUP] 1 [/SUP], Hanhui Zhong[SUP] 1 [/SUP], Xucheng He[SUP] 1 [/SUP], Yinyan Li[SUP] 1 [/SUP], Jinxiang Chen[SUP] 1 [/SUP], Jie Yang[SUP] 2 [/SUP]
Affiliations
- PMID: 42562331
- DOI: 10.1016/j.bcp.2026.118321
Influenza A virus (IAV) remains a major global health threat due to its high mutation rate and the emergence of antiviral resistance. Targeting host factors provides an alternative therapeutic strategy to overcome these challenges. Previous studies have shown that the L-type calcium channel Ca[SUB]v[/SUB]1.2 was implicated in viral infections. In this study, we aimed to clarify the mechanism by which Ca[SUB]v[/SUB]1.2 acts as a critical host factor mediating IAV infection, using the dihydropyridine-type calcium channel blocker nisoldipine. Nisoldipine showed notable antiviral activity in both in vitro and in vivo models. Mechanistically, nisoldipine inhibited IAV internalization by targeting Ca[SUB]v[/SUB]1.2, thereby suppressing calcium-dependent activation of the Ras-PI3K-AKT, RhoA-ROCK, and JNK pathways associated with viral internalization. Moreover, nisoldipine modulated the unfolded protein response (UPR) in host cells by promoting adaptive XBP1 splicing and contributed to the maintenance of endoplasmic reticulum (ER) homeostasis during IAV infection. Collectively, these observations support a sequential cascade model: Ca[SUB]v[/SUB]1.2 inhibition restrains viral entry and indirectly mitigates virus-triggered ER stress. Furthermore, nisoldipine exhibits broad-spectrum in vitro antiviral activity against multiple enveloped RNA and DNA viruses, including human coronavirus OC43 (HCoV-OC43), respiratory syncytial virus (RSV), Zika virus (ZIKV), Dengue virus Type 2 (DENV2), and Herpes Simplex Virus Type 1/2 (HSV-1/2). This study clarifies the mechanistic involvement of Ca[SUB]v[/SUB]1.2 in IAV infection and further identifies it as a promising broad-spectrum antiviral target with potential applications in preventing and treating influenza, human coronavirus infections, and other emerging viral diseases.
Keywords: Broad-spectrum antiviral activity; Host-targeted therapy; Influenza A virus; Internalization; L-type calcium channel Ca(v)1.2; Nisoldipine.