Transient receptor potential channels in viral infectious diseases: Biological characteristics and regulatory mechanisms

Graphical abstract

Highlights

• •TRP channels are involved in the regulation of viral infectious diseases.
• •The expression and function of TRP channels changes during viral infection.
• •TRP channels in host cells can be used by viruses to promote their life cycle, including entry, transport, replication and export.
• •Dysregulation of TRP channel expression and function leads to host immune and inflammatory response and then pose a threat to individual health.
• •The mechanism of TRP channels in viral infectious diseases is still on the way, and it may be beneficial for the treatment of viral infections by regulating the host TRP channels.

Abstract

Background

Viral infectious diseases have long posed a challenge to humanity. In recent decades, transient receptor potential (TRP) channels have emerged as newly investigated cation channels. Increasing evidence suggests that TRP channel-mediated Ca²⁺ homeostasis disruptions, along with associated pathological changes, are critical factors in the onset and progression of viral infectious diseases. However, the precise roles and mechanisms of TRP channels in these diseases remain to be systematically elucidated.

Aim of Review

The aim of this review is to systematically summarize recent advances in understanding TRP channels in viral infections, and based on current progress and challenges, propose future directions for research.

Key Scientific Concepts of Review

This review summarizes the classification and biological functions of the TRP family, explores the mechanisms by which TRP channels contribute to viral infections, and highlights specific mechanisms at three levels: virus, host, and outcome. These include the direct role in viral biology and replication, the indirect role in host immunity and inflammation, and the resulting pathological changes. Additionally, we discuss the potential applications of the TRP family in the treatment of viral infectious diseases and propose future research directions.

Introduction

Viral infections are among the most difficult diseases to treat, often triggering inflammatory storms, tissue and organ damage, and, in severe cases, death [1]. Viruses are classified into seven types based on their genetic material and replication processes, including double-stranded DNA viruses (dsDNA), single-stranded DNA viruses (ssDNA), double-stranded DNA retroviruses (dsDNA-RT), double-stranded RNA viruses (dsRNA), sense single-stranded RNA viruses (+ssRNA), antisense single-stranded RNA viruses (−ssRNA) and single-stranded RNA retroviruses (ssRNA-RT) [2]. Despite the fact that mankind has been fighting them for thousands of years, there is still no way to defeat it [3], [4]. While existing treatments, such as HAART, have significantly improved patient outcomes, they are ineffective in advanced disease stages, often accompanied by severe side effects and drug dependence, limiting their clinical use [5]. Therefore, it is crucial to identify new therapeutic targets with potential for drug development. Immunomodulators, which are widely used in clinical settings, play a key role in treating viral infectious diseases, suggesting that modulation of the body's internal environment may represent a promising therapeutic strategy [6].

Calcium ions (Ca²⁺) are essential for nearly all physiological processes in the human body [7]. Research has shown that viral infections often lead to dysfunction in host cells, accompanied by abnormal intracellular Ca²⁺ concentrations [8]. Calcium channels, which directly mediate Ca²⁺ transport, play a critical role in both physiological and pathological processes [9]. Over the past few decades, transient receptor potential (TRP) channels have emerged as multimodal cation channels with a significant preference for Ca²⁺. These channels are crucial for maintaining intracellular and extracellular Ca²⁺ homeostasis [10]. Recent evidence suggests that TRP-mediated Ca²⁺ dysregulation and the resulting physiological and pathological changes are key factors in the development of viral infectious diseases, making this a prominent research area. Importantly, TRP channels have gained attention in the pharmaceutical industry due to their subtype selectivity and broad biological functions, providing a foundation for the development of novel drugs targeting these channels [11], [12].

The biological functions of TRP channels in viral infectious diseases remain a key focus of research prior to drug development. In this review, we summarize the classification and biological roles of the TRP family, explore the mechanisms by which TRP channels contribute to viral infections, and highlight specific mechanisms at three levels: virus, host, and outcome. We discuss both the direct roles of TRP channels in viral biology, including viral entry, transport, replication, and egress from cells, as well as their indirect roles in host immune and inflammatory responses. Additionally, we examine the outcomes of infection, such as cell damage, fibrosis, and carcinogenesis. The goal is to deepen our understanding of the significance of TRP channels in viral infectious diseases, thereby facilitating the discovery of potential therapeutic targets and drug development.

Major TRP channel types

TRP biology, function, tissue and cell distribution

Transient receptor potential (TRP) channels were first discovered in Drosophila in 1969 and function as sensors for various cellular and environmental signals [13], [14]. Channel activity is influenced by several physical parameters, including osmotic pressure, pH, mechanical force, and external biochemical interactions such as ligands or cell proteins [15]. Based on sequence homology, TRP channels in mammals are subdivided into six subfamilies (Fig. 1): canonical (TRPC, TRPC1-7), vanilloid (TRPV, TRPV1-6), ankyrin (TRPA, TRPA1), melastatin (TRPM, TRPM1-8), mucolipin (TRPML, TRPML1-3), and polycystin (TRPP, TRPP2, P3, P5) [16]. As cation channels, they exhibit selectivity for Ca²⁺, Na⁺, and Mg²⁺ [17]. Most TRP subfamilies are more selective for Ca²⁺ and play a crucial role in maintaining the stability of intracellular and extracellular Ca²⁺ concentrations [10].

Fig. 1.

Structure and function of TRP channels. The TRP channel families share a common transmembrane structural unit and differ in the intracellular N- and C-terminal domains. TRP channels consist of six transmembrane domains (S1-S6). Formation of a channel between S5 and S6 regulates cation entry. Ligands can bind to the S1-S4 domain to regulate channel opening or closing. The specific structural characteristics of each subtype have been systematically reviewed elsewhere and will not be discussed here [37]. Based on their distinct structures and broad distribution throughout the human body, TRP channels form functional homotetramers that perform diverse functions. This figure was created using BioRender.

TRPC. TRPC channels (with TRPC2 being a pseudogene in humans) were the first identified members of the TRP family [18]. The remaining isoforms are organized into two subsets of functional heterodimers: TRPC1 forms heteromers with TRPC4 and TRPC5, while TRPC3 forms heteromers with TRPC6. These channels play important roles in regulating the balance of various cations inside and outside cells [19]. TRPC channels are expressed in the hippocampus, salivary glands, heart, vascular smooth muscle, pancreatic β cells, and kidneys, where they regulate signal transduction in the nervous and cardiovascular systems, as well as the immune response [20]. A study by Li et al. found that, in addition to regulating Ca²⁺ signaling in cardiomyocytes, TRPC1 and TRPC6 also enhance the TLR-NF-κB inflammatory pathway via calmodulin (CaM), a protein essential for the integrity of this pathway [21], [22].

TRPV. TRPV channels, named for their sensitivity to vanilloids and capsaicin, allow Ca²⁺ entry when activated by capsaicin or bound to the specific ligand resiniferatoxin (RTX). Additionally, they can be activated by various physical and chemical stimuli, including heat, pressure, pH, and pathogenic microorganisms such as lipopolysaccharides [23]. The thermosensitive TRPV1-4 channels are present in both neuronal and non-neuronal cells, primarily endothelial and immune cells (e.g., dendritic cells and T cells), where they play roles in thermal sensation, osmotic or mechanosensation, neuronal development, and proinflammatory processes related to neurogenic inflammation and hypersensitivity [24].

TRPA1. TRPA1, regulated by the oxidant-defense transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), acts as a sensor for various internal and external noxious stimuli, including extreme cold, irritating compounds, mechanical forces, reactive chemicals such as reactive oxygen species (ROS), and endogenous signals linked to cell damage [25]. Although the role of TRPA1 as a temperature sensor remains debated, it is now understood that its sensitivity to extreme cold is indirect. Severe cold induces the release of TRPA1-activating chemical agonists, such as Ca²⁺ and ROS, which further activate TRPA1 and link it to the perception of cold stimuli [26]. TRPA1 is expressed in nociceptive sensory neurons and non-neuronal cells, including fibroblasts, inner ear hair cells, satellite glial cells, and Schwann cells, and is involved in the regulation of pain, hypersensitivity, and neurogenic inflammation [27].

TRPM. TRPM channels are involved in processes related to cell proliferation and cancer development. TRPM1 was first identified in a mouse melanoma cell line due to its reduced expression [28]. TRPM2, associated with autophagic-apoptotic gene expression, was overexpressed in human prostate cancer samples [29]. TRPM6 and TRPM7 were abundantly expressed in colorectal cancer, with TRPM7 expression positively correlating with tumor grade [30]. Beyond regulating cell growth, development, and death, many TRPM members are also involved in the regulation of neurological diseases, temperature sensing (TRPM8, an antagonist of TRPV1, is known as a cold and menthol receptor), endothelial dysfunction, inflammation, type II diabetes, and other conditions [31].

TRPML. TRPML channels, whose expression is regulated by transcription factor EB (TFEB), are ion channels located on intracellular vesicles involved in trafficking. In addition to regulating processes such as phagocytosis, autophagy, and lysosomal exocytosis, TRPML channels also help maintain pH balance within lysosomes, enabling proper degradation functions [32]. Pathophysiologically, mutations in TRPML1 lead to the neurodegenerative lysosomal storage disease-type IV mucolipidosis, and gain-of-function mutations in TRPML3 cause Duenne muscular dystrophy. Furthermore, TRPML channels are implicated in infectious diseases, immune responses, cancer, and pigmentation disorders [33].

TRPP. TRPP channels (TRPP2, TRPP3, and TRPP5) are significant members of the TRP family [34]. Substantial evidence suggests that the TRPP subfamily is involved in the development of autosomal dominant polycystic kidney disease in humans [35].

In summary, TRP channels are present in various tissues, organs, and cells, and are localized not only on cell membranes but also on subcellular organelle membranes, where they participate in diverse physiological and pathological processes [36].

TRP channel modulators in clinical

Given the wide range of physiological and pathological roles that TRP channels play in the body, targeting these channels with specific modulators can regulate protein activity and potentially provide therapeutic benefits. Currently, modulators targeting TRPV1 (NEO6860 for the treatment of osteoarthritic pain), TRPV3 (GRC 15,300 for the treatment of pain [12]), TRPV4 (GSK-2798745 for the treatment of heart failure [38], [39]), TRPV6 (SOR-C13 for the treatment of anti-advanced refractory solid tumors [40], [41]), TRPA1 (A-967079 [42], ISC-17536 [43], and LY-3526318 [44] for the treatment of pain), TRPM8 (PF-05105679 for pain [12]), TRPC4 and TRPC5 (BI 1,358,894 for the treatment of anxiety and depression [45]) have entered clinical trials. These developments suggest that TRP channels hold significant clinical value as therapeutic targets, and their pharmacological modulation has great potential for disease treatment.

However, no drugs targeting TRP channels are currently available for the treatment of viral infectious diseases. Table 1 lists TRP expression and function in viral infections, along with modulators under preclinical investigation. Additionally, the main associations between common viruses and TRP channels are illustrated in Fig. 2.

Table 1.

Expression and function of TRP channels and modulators in viral infection.

Channel	Expression	Experimental model	Findings regarding to viral infectious diseases	Modulator and IC50 value	Reference
TRPC1	Upregulation	HSV-1 infection in HEp-2 cells; HSV-1 infection in Tpc1 knockout mice and patients with oral herpes lesion; Pharmacological blockade of TRPC1 in HEp-2 cells	Promoting Viral entry and infection	C1E3p [A synthetic peptide, containing the third ectodomain (amino acids 608 to 616) of TRPC1]	[51]
TRPC3	Upregulation	SARS-CoV-2 infection in NRCM cells; Pharmacological blockade of complex between TRPC3 and Nox in NRCM cells	Promoting Viral entry and infection	Ibudilast	[46], [56]
TRPV1	Upregulation	TRPV1 siRNA mediated silence in RSV infected HBE cells; Pharmacological activation of TRPV1 in RSV infected HBE cells	Promoting inflammatory response	Capsaicin	[85]
TRPV1	Upregulation	HRV-16 infection in IMR-32 neuroblastoma cells	Responding to inflammatory response	−	[72]
TRPV1	Upregulation	RSV infection in C-fibers and AMs	Promoting inflammatory response	−	[86]
TRPV1	Upregulation	HSV-2 infection in DRG	Promoting thermal pain sensitivity	−	[87]
TRPV1	Activaiton	ZIKV infection	Responding to and promoting inflammatory response	Capsaicin	[89]
TRPV1	Activation	CVB3 infection in Hela cells and IBECs; Pharmacological inhibition of TRPV1 in IBECs	Promoting viral entry and infection	SB-366791	[73]
TRPV1	Upregulation and Activation	HIV infection in monocyte-derived LCs and CD4+ T cells	promoting inflammatory response and anti-virus functions	A425619 (TRPV1 antagonist); capsaicin or CGRP (TRPV1 agonist)	[94]
TRPV2	Upregulation	SARS-CoV-2 infection in PBAMs, RAW264.7 and THP-1 human cells; Trpv2 shRNA mediated silence in PBAMs; Pharmacological blockade of TRPV2 in PBAMs	Promoting viral entry and infection; Inducing inflammatory response	SKF-96365	[57]
TRPV2	Upregulation	HSV-1 and VSV infection in Trpv2 knockout myeloid cells; Pharmacological blockade of TRPV2 in myeloid cells	Promoting Viral entry and infection	SKF96365	[58], [59]
TRPV4	Activation	Using trophoblasts as a model for cell fusion in HIV and SARS-CoV2 infection; Pharmacological inhibition or siRNA silencing of TRPV4	Promoting virus-mediated syncytialization	GSK1016790A (TRPV4 specific agonist); GSK2193874 (GSK219, a selective TRPV4 antagonist)	[60]
TRPV4	Activation	Pharmacological activation of TRPV4 in ISKNV infected MFF-1 cells	Promoting viral replication	RN-1747	[75]
TRPV4	Upregulation	TRPV4 siRNA mediated silence in HBV infection HepAD38 cells	Promoting viral replication; Cancerization	HC-067047 (TRPV4 inhibitor)	[47]
TRPV4	Activation	Genetic depletion or pharmacological inhibition of TRPV4 in dengue, hepatitis C and ZIKV	Promoting viral replication	GSK1016790A (TRPV4 specific agonist); HC067047 (TRPV4 inhibitor)	[76]
TRPV4	Activation	Pharmacological inhibition of TRPV4 in ZIKV infected HeLa cells	Promoting virus infectivity	GSK1016790A (TRPV4 specific agonist); HC067047 (TRPV4 inhibitor, IC50 of 499 nM); NSC151066 (TRPV4 inhibitor, IC50 of 145 nM)	[77]
TRPV4	Activation	SARS-Cov-2 infection in PAECs and hACE2 Tg mice	Inducing cell damage	GSK2798745 (TRPV4 antagonist)	[100], [106]
TRPA1	Upregulation	HRV-16 infection in IMR-32 neuroblastoma cells	Responding to inflammatory response	−	[72]
TRPM2	Upregulation	Huh-7 cells were transfected with the pHBV1.3 plasmid; HBV infection in TRPM2 siRNA silencing Huh-7 cells	Promoting viral replication; Inducing cell damage	−	[71], [120]
TRPM4	Upregulation	HIV infection in SNB19 cell lines; HIV-infected postmortem human and transgenic Tg26 mouse brain tissue	promoting inflammatory response; Inducing cell damage	−	[96]
TRPM4	Upregulation	HBV-related HCC patients	Cancerization	−	[139]
TRPM8	Upregulation	HRV-16 infection in IMR-32 neuroblastoma cells	Responding to viral replication	−	[72]
TRPMLs	Activation	Pharmacological inhibition of TRPML in JEV infected A549 cell lines	Promoting viral entry, egress and infection	Berbamine	[64]
TRPMLs	Upregulation	Pharmacological activation of TRPML in DENV2 and ZIKV infected A549 cell lines	Promoting viral entry and infection	ML-SA1 (TRPMLs agonist; IC50 value against DENV2 RNA was 8.93 μM; IC50 value against ZIKV RNA was 52.99 μM); SN-2 (TRPML3 agonist)	[65], [66]
TRPML2	Upregulation	Trpml2 knockout mice and RAW 264.7	Activation of the immune response, including secretion of chemokines and immune cell migration	−	[80]
TRPML3	Activation	SARS-CoV-2 infection in TRPML3 siRNA silencing HeLa cells	Promoting viral egress and infection	−	[69]

Fig. 2.

Main associations between common viruses and TRP channels. (A) HIV is a type of retrovirus that attacks and gradually destroys the human immune system. In the early stages of HIV infection, the body's inflammatory response is pronounced, and patients often exhibit neuroinflammation and neurological dysfunction. HIV initially targets antigen-presenting cells (APCs), which present the virus to CD4⁺ T cells. Infected immune cells release inflammatory factors, which, along with HIV itself, compromise the integrity of the BBB, allowing the virus to invade the CNS and cause CNS inflammation. Antiretroviral drugs (ARVs) are known to have limited ability to penetrate the BBB, leading to a persistent increase in CNS viral load and irreversible neurological damage. TRPV1 and TRPML activation, as well as TRPM inhibition, have been shown to exert anti-HIV effects and mitigate its complications, suggesting that TRP channels play a role in HIV-related diseases. (B) TRPV2, expressed in macrophages activated by SARS-CoV-2, regulates chemokine production, responses to chemokines, adhesion, and migration from the bloodstream to sites of lung and heart injury. Additionally, TRPC3 is involved in other cellular responses that contribute to SARS-CoV-2 susceptibility. (C) Neuronal TRPV1 can be activated by inflammatory factors and encephalitis viruses, promoting neuroinflammation, secretion of inflammation-related neuropeptides, and neuronal damage. These neuropeptides activate peripheral immune cells, leading to the release of additional inflammatory factors and chemokines, which recruit more immune cells to invade the CNS. (D) Viral hepatitis, caused by a variety of hepatitis viruses (HAV, HBV, HCV, HDV, and HEV), can progress to liver failure, fibrosis, cirrhosis, and liver cancer. Different TRP channels are involved at various stages of disease progression. This figure was created using Figdraw.

Direct role of TRP channels in viral biology and replication

Viruses, as foreign pathogens, can hijack TRP channels within host cells to facilitate their entry, transport, replication, and export through various pathways. In the following sections, we will explore common viral infections in which TRP channels play a role in viral biology and replication (Fig. 3).

Fig. 3.

TRP channels are involved in the viral life cycle. (1) The third ectodomain of TRPC and TRPV2, as host receptors for viral attachment, mediates viral endocytosis into host cells, involving SOCE-mediated intracellular calcium overload. Additionally, viruses can exploit TRPV4 to promote their endocytosis into host cells. (2) TRPML allows viral particles trapped in vesicles to escape from fusion with late endosomes and lysosomes, preventing their subsequent clearance. (3) Once the viral particles have escaped, they release their DNA or RNA genetic material, which utilizes host proteins and organelles to complete replication, transcription, translation, and assembly. During this process, cytoplasmic TRPM promotes viral replication by regulating autophagy. Furthermore, TRPV4 not only promotes viral protein stabilization through the ubiquitination pathway but also associates with RNA polymerase to facilitate RNA virus replication. (4) The assembled virus is transported out of the cell via TRPML. This describes the complete viral life cycle facilitated by host TRP channels. This figure was created using Figdraw.

TRP channels as receptors at viral entry into host cells

The attachment of viral particles to the plasma membrane, followed by their penetration into the cytoplasm, constitutes the first steps of effective viral infection in the host [48].

TRPC. STIM1 and Orai1 alone are insufficient to maintain Ca²⁺ homeostasis. The TRPC1 channel, as a component of the SOC channel, plays a role in regulating dynamic changes in intracellular Ca²⁺ concentration [49], [50]. In its resting state, TRPC1 is localized in both the plasma membrane and the cytosol. To meet the virus’s requirement for Ca2⁺, Ca2⁺ influx via Orai1 has been reported to induce the translocation of intracellular TRPC1 to the plasma membrane, where it acts as a viral receptor, mediating the entry of viruses like herpes simplex virus type 1 (HSV-1, a dsDNA virus), the most common cause of viral encephalitis. Further studies reveal that the third ectodomain of TRPC1 interacts with HSV-1 glycoprotein D to facilitate viral entry [51]. Structurally, TRPC1 functions as a sensor of external stimuli due to its unique extracellular transmembrane domain [52]. Inhibition of Ca²⁺ entry or knockdown of TRPC1 can reduce viral entry and infection. However, TRPC1 is not the primary receptor, as TRPC knockout does not have a greater effect on HSV-1-induced Ca²⁺ influx compared to intervention with SOCE [51]. Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, a + ssRNA virus) [53]. Several studies have shown that SARS-CoV-2 not only causes lung injury but also affects extrapulmonary organs, particularly the cardiovascular system [54], [55]. The abundance of ACE2 is believed to reflect susceptibility to infection. ACE2 is expressed in both the lungs and the heart, providing the basis for SARS-CoV-2 to infect cardiac tissue. TRPC channels are widely expressed in the heart, and research has shown that SARS-CoV-2 induces the formation of the TRPC3-Nox2 complex, which promotes ROS production. Dysregulated ROS production leads to oxidative stress in cardiomyocytes, upregulating ACE2 expression and increasing susceptibility to SARS-CoV-2 infection, ultimately causing myocardial damage [56].

TRPV2. A study has shown that TRPV2 acts as a receptor for SARS-CoV-2 at elevated temperatures, and the co-presence of heat and SARS-CoV-2 promotes TRPV2 activation in macrophages, facilitating viral entry and cytokine secretion. Inhibition of TRPV2 effectively blocks macrophage migration and reduces the virus-mediated inflammatory response in primary bovine alveolar macrophages (PBAMs), RAW264.7, and THP-1 cells [57]. Furthermore, TRPV2-mediated expression of LRMDA increases myeloid membrane tension and fluidity, aiding the entry of HSV-1 and vesicular stomatitis virus (VSV) into myeloid cells via endocytosis [58], [59]. Viruses that enter cells via non-endocytic pathways allow the viral capsid to enter the cytoplasm through membrane fusion, forming syncytia. Recent studies have shown that TRPV4-mediated Ca²⁺ influx in viral diseases directly activates TMEM16F, which plays a role in human immunodeficiency virus (HIV, a ssRNA-RT virus) infection and SARS-CoV-2-mediated syncytialization [60]. Therefore, TRPV channels, primarily located in immune cells, not only act as viral receptors but also influence cell membrane dynamics, mediating viral entry into host cells.

TRPML channels in viral cytoplasmic transport

Viral vesicular trafficking and subsequent escape from endosomal compartments are critical processes for successful infection of host cells. Although TRPML channels are primarily located in membrane-bound vesicles associated with endocytic and exocytic pathways, only TRPML2 and TRPML3 have been found to enhance viral infection [61], [62], [63].

TRPLM2/3 functions when viruses enter the cell. Recent research has demonstrated that inhibiting the TRPML family to impair lysosomal function can prevent japanese encephalitis virus (JEV, a + ssRNA virus) from entering host cells. This is achieved by inhibiting the fusion between virus-containing late endosomes and lysosomes, which blocks viral trafficking, while simultaneously promoting the release of the virus from the cell in the form of extracellular vesicles [64]. Huang et,al found that Berbamine inhibits JEV infection by blocking endolysosomal TRPMLs [64]. However, treatment with ML2-SA1 and SN-2, two selective agonists for TRPML2/3, inhibits Dengue virus type 2 (DENV2) and Zika virus (ZIKV, a + ssRNA virus) by promoting lysosomal acidification and protease activity. As expected, neither ML2-SA1 nor SN-2 inhibited HSV-1, whose entry is independent of the endo-lysosomal network [65], [66]. TRPML agonists can promote the fusion of viruses with lysosomes, while inhibitors block vesicular transport and promote the expulsion of virus particles from host cells in the form of exosomes. In summary, TRPML regulators exhibit antiviral effects in completely opposite but distinct ways. Due to the varying functions of host cells and differences in viral life cycles, further studies are needed to elucidate the precise mechanisms involved.

TRPM3 functions when virus particles are released from the host cell. Virus exocytosis is a key determinant of viral infectivity and pathogenicity. TRPML3 can sense lysosomal contents, trigger Ca²⁺ efflux, and stimulate lysosomal exocytosis [67]. However, a previous study showed that when TRPML3 was knocked down, Ca²⁺ still accumulated near the cell membrane, but lysosomal exocytosis was inhibited [68]. This suggests that while TRPML3 is not responsible for localized lysosomal Ca²⁺ release, it is essential for triggering the fusion of lysosomes containing SARS-CoV-2 with the plasma membrane and facilitating subsequent lysosomal exocytosis [69]. As previously mentioned, Berbamine can also inhibit the release of JEV particles by blocking TRPML function [64].

TRP channels in viral replication

TRPM. Over long-term evolution, viruses have developed various mechanisms not only to escape, destroy, and inhibit autophagy to protect themselves but also to exploit the host's autophagy processes to enhance their replication and improve adaptability to the environment [70]. TRPM2, induced by HBV, interacts with P47phox also called neutrophil cytosolic factor 1 (NCF1), which is required for activating latent NADPH oxidase, leading to autophagy and facilitating HBV replication. TRPM2 knockdown has been shown to decrease HBV viral load and reduce the secretion of HBeAg, HBsAg, and autophagic flux both in vitro and in vivo [71]. Additionally, Abdullah et al. highlighted that upregulation of TRPM8 is associated with the replication of respiratory viruses, such as rhinovirus (HRV-16), in neuronal cells. Specifically, TRPM8 expression, which triggers coughing, is induced following viral replication. It is speculated that viral RNA, replication intermediates, or nonstructural viral proteins may activate signaling pathways upstream of TRPM8 in infected cells [72]. However, the upstream events that trigger TRPM8 in response to viral infection remain an area for further investigation.

TRPV. TRPV4 can enhance HBV replication by hijacking Ca²⁺-related host proteins. Mechanistically, TRPV4 promotes HBc protein stability through post-translational modification and increases cccDNA-dependent transcription by promoting H3K4 methylation [47]. SB-366791, a TRPV1 inhibitor, has been reported to significantly reduce CVB3 infection and protect the integrity of induced pluripotent stem-cell (iPSC)-derived brain endothelial-like cells (iBECs), limiting viral entry into the brain and reducing neuronal damage [73]. Additionally, RNA viruses rely on host cell proteins for RNA metabolism. RNA helicases, multifunctional proteins that catalyze different steps in RNA metabolism, are essential for this process [74]. DDX, a widely expressed DEAD-box RNA-binding helicase, interacts with TRPV4 under normal physiological conditions. However, proteins from the infectious spleen and kidney necrosis virus (ISKNV) activate TRPV4, leading to the separation of TRPV4 from DDX. The free DEAD-box RNA helicase 1 (DDX1) then becomes involved in RNA virus replication [75]. Similarly, activated TRPV4 translocates from the cytoplasm to the plasma membrane, mediating Ca²⁺ influx, which drives the nuclear translocation of DDX3X via CaM and CaM-dependent kinase II, promoting RNA virus replication [76]. This suggests that TRP channels in the cytoplasm may have mechanisms distinct from their role as membrane proteins. Notably, mouse embryonic fibroblasts with TRPV4 gene knockouts, or treated with the pharmacological inhibitor HC067047, showed a significant reduction in the infectivity of DENV2, HCV, and ZIKV, with no changes in cellular viability [76]. A drug screening study identified the compound NSC151066 as capable of inhibiting ZIKV in HeLa cells by targeting TRPV4 [77]. These findings suggest that gene therapy and pharmacological inhibition of TRPV4 could provide therapeutic benefits for patients with viral infectious diseases.

Indirect role of TRP channels as in host immunity and inflammation

Viral invasion is accompanied by activation of the host immune response and storm of inflammation [78]. Pattern recognition receptors (PRRs), including the membrane-bound Toll-like receptors (TLRs), C-type lectin receptors, retinoid acid-inducible gene-1-like receptors (RLRs), and nucleotide oligomerization domain (NOD)-like receptors (NLRs), exist in innate immune cells for recognition of viral components and cellular components damaged by viruses [79]. Increasing evidence suggests a reciprocal regulatory role between PRRs and TRP channels in response to viral infection, contributing to immune responses and cytokine release syndrome (CRS).

TRPMLs play a double-edged sword role in viral infection

TRPML2 is expressed at low levels in resting RAW264.7 macrophages, but is strongly induced upon TLR activation, with no effect on TRPML1 or TRPML3 [80]. Increased TRPML2-mediated viral uptake in immune cells with higher basal levels of TRPML2 also leads to greater PRR activation, a stronger immune response, and improved viral clearance [81], [82]. As mentioned earlier, TRPML2 and TRPML3 are involved in viral infection processes that facilitate viral entry into host organisms. However, as research progresses, it becomes evident that TRPML plays a double-edged sword role in viral infectious diseases. On the one hand, TRPML promotes viral entry into host cells, which can be inhibited by TRPML inhibitors such as Berbamine [64]. Accumulated autophagy has been reported to induce Bcl-2/BAX-mediated apoptosis and NLRP3 inflammasome-dependent pyroptosis, leading to both cell and tissue damage (see below for the mechanism of cell damage). This “suicidal” antiviral effect may present challenges, but combination therapies hold promise for mitigating these issues. Conversely, TRPML also plays a role in antiviral immunity, which can be enhanced by TRPML agonists such as ML-SA1 [66]. Furthermore, the interaction between TRP-mediated Ca²⁺ signaling and PRRs, particularly with TLRs and NLRP3, has been thoroughly reviewed [83].

TRP in virus-induced inflammatory response

TRPVs in viral hepatitis. HBV and HCV can trigger hepatic inflammation by activating TRPV1 and TRPV3 on resident Kupffer cells, leading to chemokine-mediated recruitment of blood-borne monocytes and neutrophils. Knockdown of TRPV1 was shown to significantly reduce mRNA levels of chemokines and pro-inflammatory cytokines, as well as attenuate neutrophil infiltration. Similarly, treatment with the TRPV3 inhibitor forsythoside B notably reduced F4/80 expression on macrophages and decreased mRNA levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) in mouse liver [84].

TRPV1 in asthma induced by viral respiratory infections. Respiratory syncytial virus (RSV, an RNA virus) infection of human bronchial epithelial (HBE) cells in children significantly activates TRPV1, contributing to increased susceptibility to asthma in infected children [85]. HRV-16 has been shown to directly infect neuronal cells, resulting in the upregulation of TRPA1 and TRPV1 expression, mediated by channel-specific inflammatory factors [72]. Upregulation of TRPV1 in sensory neurons enhances the expression of pro-inflammatory neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP), contributing to neurogenic inflammation in asthmatic mice. Interestingly, inhibition of TRPV1, leading to the degeneration of C fibers, induces the production of vasoactive intestinal peptide (VIP), which modulates alveolar macrophages (AMs) to produce alpha/beta interferon (IFN-α/β), thereby reducing viral replication and alleviating lung inflammation [86]. This suggests a correlation between the peripheral and central immune systems, and combination therapies may exert a synergistic “1 + 1 > 2″ effect in treating peripheral viral infections.

TRPV1 in neurotropic virus infections. Glycoprotein G (SgG2), secreted by herpes simplex virus type 2 (HSV-2), interacts with nerve growth factor (NGF), activating its function. Activated NGF promotes the expression and membrane localization of TRPV1 in the dorsal root ganglia (DRG), thereby increasing the sensitivity of sensory neurons to pain [87]. An NGF antibody designed to block TRPV1 has completed phase II clinical trials (NCT00000842) for HIV infections and peripheral nervous system diseases [88]. It has also been shown that ZIKV-induced inflammation triggers the expression and activation of TRPV1, which further sensitizes nerve endings and aggravates the release of substance P and CGRP, creating a positive inflammatory feedback loop that leads to persistent inflammation. Moreover, TRPV1-mediated persistent Ca²⁺ entry ultimately results in apoptosis and neurotoxicity [89]. Administration of TRPV1 antagonists can suppress the inflammatory response, but intriguingly, capsaicin—known for its antioxidant and anti-apoptotic properties—can relieve pain and inhibit inflammation by degenerating C-fibers [90]. These findings suggest that TRPV1 is a key molecule linking peripheral inflammation and neuroinflammation ( Fig. 4). Targeting TRPV1, whether through agonists or antagonists, offers unique advantages in treating viral infection-induced inflammatory storms.

Fig. 4.

TRPV1 is a key molecule connecting peripheral inflammation and neuroinflammation. (1) Viruses in peripheral blood invade and activate immune cells; (2) Activated immune cells release inflammatory factors that destroy the integrity of the BBB, leading to virus invasion and immune cell infiltration of the CNS; (3) Released inflammatory factors and viruses can activate glial cells, and activated glial cells can also secrete inflammatory factors; (4) Neuronal TRPV1 can be activated by inflammatory factors and viruses (5) to subsequently promote neuroinflammation, secretion of inflammation-related neuropeptides (Substance P and CGRP, etc.) and neuronal damage; (6) The neuropeptides that are triggered activate peripheral immune cells to release more inflammatory factors (TNF-α, IL-1β, histamine and IFN-γ) and chemokines, and (7) chemokines recruit more immune cells to invade the CNS. Thus, a positive feedback system of inflammation was formed with TRPV1 as the focus. This figure was created using Figdraw.

TRPV1 in AIDS. Acquired immune deficiency syndrome (AIDS) is an infectious disease caused by the HIV, a ssRNA-RT virus, which attacks and gradually weakens the human immune system, leaving the host vulnerable to secondary infections and cancer, often leading to death [91]. HIV primarily invades CD4⁺ T cells, as well as antigen-presenting cells (APCs), including dendritic cells, monocytes, macrophages, and Langerhans cells, which can transfer the virus to CD4⁺ T cells [92]. HIV induces T cells to secrete the chemokine CCL5, mediating T-cell recruitment to the epidermis to receive antigen delivery from APCs [93]. TRPV1 is highly expressed in monocyte-derived Langerhans cells (MDLCs), and studies have shown that activation of TRPV1 with capsaicin induces the secretion of CGRP, which mediates anti-HIV-1 effects by increasing CCL3 secretion and modulating CCR5 expression, leading to the recruitment of T cells [90]. Thus, TRPV1 activation enhances viral antigen presentation by increasing CCR5 expression and promoting its interaction with CCL5-secreting T cells, providing an anti-mucosal HIV infection response [94]. These findings suggest that TRPV1-mediated inflammatory and antiviral responses are interconnected, which may explain why both TRPV1 agonists and antagonists show efficacy in treating viral infections.

TRPM4 and TRPML involvement in HIV-associated neurocognitive disorders (HAND). It is not difficult to imagine that inflammatory factors and HIV can further compromise the integrity of the BBB, allowing the virus to invade the CNS and cause CNS inflammation. A new challenge for many HIV-infected individuals on treatment is chronic neuroinflammation and neurotoxicity, often leading to HAND [95]. Studies have shown that TRPM4 is upregulated in the brain tissues of HIV-infected animals and humans, potentially contributing to HIV-induced activation of proinflammatory markers (TLR4, TNF-α, and NF-κB) and apoptosis in astrocytes [96]. Additionally, the accumulation of amyloid-beta (Aβ) peptides in the lysosomal and autophagic compartments of neurons has been observed in the brains of HIV-infected patients, which is a contributing factor to cognitive impairment [97]. Activation of TRPML1 induces the release of intraluminal calcium, resulting in reduced endolysosomal pH, sphingomyelin levels, and Aβ accumulation [98].

The findings above suggest that TRP channels play a broad role in virus-induced immune responses (Fig. 5), with TRPV1 serving as a key molecule connecting neurons and the immune system. Regulation of TRPV1 on neurons or immune cells plays a crucial role in modulating both inflammation and antiviral immunity. These studies highlight the therapeutic potential of strategies aimed at balancing antiviral immunity and inflammatory responses.

Fig. 5.

TRP channels are involved in the host antiviral immune and inflammatory response. During this process, TRPC activation and Ca²⁺ influx are involved, with downstream CaM supporting TLR activation and its downstream NF-κB inflammatory pathway. However, knockdown of TRPC or the use of TRPC inhibitors has been shown to have anti-inflammatory effects by disrupting the binding of CaM to the TLR4 protein, thereby blocking TLR4 receptor activation and inhibiting MyD88- and TRIF-dependent inflammation. Additionally, TRPC, TRPV, TRPA1, and TRPM channels are involved in the activation of the NLRP3 inflammasome, as well as the JAK-STAT and PI3K-mTOR antiviral signaling pathways. This figure was created using Figdraw.

Role of TRP channels in outcome of viral infection or individual health

Given that viruses exploit TRP channels to support their life cycles in host cells and that TRP channels are involved in both host immune responses and excessive inflammatory reactions, it is not surprising that infected cells respond to abnormal changes in TRP channels, resulting in various pathological outcomes. These include cellular damage, fibrosis, and carcinogenesis, all of which can have profound effects on individual health.

TRP channels in host cellular damage

Various forms of cell death contribute to host cell injury, including apoptosis, necrosis, pyroptosis, and ferroptosis, each driven by distinct signaling cascades [99]. TRP channels play a role in responding to viral-induced tissue and organ damage, as well as in regulating these modes of cell death (Fig. 6).

Fig. 6.

TRP channels are involved in virus-induced cell death. Cytosolic Ca²⁺ is involved in Caspase death-related signaling pathways and AMPK metabolism-related signaling pathways. The presence of TRP channels in the cytosol and envelope may play diametrically opposite roles in transporting Ca²⁺, thereby participating in the regulation of relevant signaling pathways to induce cell death. This figure was created using Figdraw.

TRP cnannels in cell apoptosis. The extrinsic (death receptors, including TNFR, FasR, TRAIL R1/R2) and intrinsic (mitochondria, including Bcl-2/Bax) apoptosis pathways converge at the mitochondria, culminating in the formation and activation of the apoptosome.Yang et al. demonstrated using hAce2 mice and cultured human pulmonary arterial endothelial cells (PAECs) in vitro that ACE2-mediated viral entry into host cells induces apoptosis by acutely activating TRPV4, increasing Bax/Bcl-2 protein expression, and forming clusters with Orai1, Piezo1, and TRPC1. This facilitates the activation of Piezo1 and store-operated calcium channels (SOCC), disrupting calcium homeostasis in pulmonary vascular endothelial cells [100]. When cytoplasmic Ca²⁺ concentration rises, mitochondria accelerate Ca²⁺ uptake [101], leading to phosphate ion deposition, which impairs ATP synthesis and mitochondrial energy metabolism, and increases ROS production, resulting in oxidative stress [102]. Elevated ROS promotes the activation of PARP-1, which catalyzes the cleavage of NAD⁺ into nicotinamide and ADPR. ADPR then binds to and activates TRPM2 channels, allowing more Ca²⁺ to enter the cells, thereby forming a positive feedback loop of oxidative stress and apoptosis [103], [104]. Simultaneously, cytochrome C is released from mitochondria, subsequently activating Caspase-9 and Caspase-3, leading to apoptosis [105]. A selective TRPV4 inhibitor, GSK2798745, has been shown to be effective and safe for patients suffering from cardiogenic lung edema [106]. Additionally, Wegierski et al. demonstrated that TRPP2, located on sub-organelle membranes, protects cells from apoptosis by reducing Ca²⁺ release from the ER and inhibiting the Calpain-Caspase 12, the c-Jun N-terminal kinase (JNK), and CHOP pathways [107]. Taken together, the dynamic localization of TRP channels in the plasma membrane or subcellular compartments [108] suggests that TRP channels may play opposing roles depending on their cellular location, which could serve as a promising strategy for treating viral infections, warranting further investigation.

TRP channels in cell necrosis. There is evidence that vaccinia virus (VV) [109], influenza A virus (IAV) [110], and SARS-CoV-2 are associated with cell necrosis. Studies have shown that SARS-CoV-2 can directly interact with receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3), promoting their activation and recruiting MLKL and PGAM5 [111], [112]. Additionally, TRPM7 has been reported as a downstream target of MLKL, mediating Ca²⁺ influx and subsequent PM damage [113]. Furthermore, treatment with the TRPV1 agonist capsaicin can induce cell necrosis in A2058 and A375 cells through the upregulation of RIP3 [114]. This result suggests that TRPV1 plays different roles in different cells. In immune cells, TRPV1 has antiviral and inflammatory effects, while in non-immune cells, TRPV1 not only mediates virus invasion into host cells but also participates in the induction of host cell necrosis.

TRPM2 channels in cell pyroptosis. Accumulating evidences have shown that virus protein can regulate inflammasome activity. For example, during CD16 and ACE2 receptor-mediated infection, the SARS-CoV-2 N protein interacts with NLRP3 to promote the interaction between NLRP3 and ASC. This further recruits procaspase-1 to form inflammasome complexes, leading to the production of active caspase-1. Caspase-1 then cleaves pro-IL-1β and pro-IL-18 into their active forms, IL-1β and IL-18, while also cleaving gasdermin-D (GSDMD) to form the GSDMD-N terminal domain, which inserts into the cell membrane to create GSDMD pores. These pores trigger pyroptosis and the release of inflammatory factors [115], [116], [117]. As mentioned earlier, viral proteins can activate TRP channels, promoting Ca²⁺ accumulation in the cytoplasm. Previous studies have shown that Ca²⁺ imbalance not only directly activates the NLRP3 inflammasome but also enhances mitochondrial ROS production, with excess ROS further contributing to NLRP3 inflammasome-related pyroptosis [118], [119]. Similarly, TRPM2-mediated Ca²⁺ influx and elevated ROS levels can directly activate the NLRP3 inflammasome, participating in pyroptosis [120], [121].

TRP channels in Ferroptosis. Ferroptosis is implicated in the pathogenesis of SARS-CoV-2-induced lung injury [122], [123], HIV-induced microglia death [124], and HBV-induced hepatocellular carcinoma development [125]. Mechanistically, iron overload resulting from impaired iron transport leads to mitochondrial ROS generation. The generated ROS then form lipid free radicals, which react with polyunsaturated fatty acids (PUFAs) to synthesize phospholipid hydroperoxides (PLOOHs), a process mediated by acyl-CoA synthetase long-chain family member 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and lipoxygenases (LOXs), collectively known as lipid peroxidation [126]. Lipid peroxidation increases membrane tension, activating Piezo1 and TRP channels, which leads to non-selective cation influx, cell swelling, and ultimately membrane rupture. Inhibition of TRP-mediated cation changes has been shown to attenuate ferroptosis in infected cells [127].

TRP channels in tissue fibrosis

The liver and lungs are the major organs affected by virus-associated fibrotic complications. SARS-CoV-2-induced COVID-19 in the lungs [128], HBV/HCV induced hepatitis B and C in the liver [129], and picornavirus and HRV-16 closely associated with cystic fibrosis [130] are reported to be major types of viruses causing fibrosis. Several signaling pathways involved in fibrosis include the canonical TGF-β/Smad-2/3 pathway and non-canonical pathways, such as Wnt/β-catenin, PI3K/Akt/mTOR, p38 MAPK, and NF-κB pathways. These pathways lead to increased production of α-smooth muscle actin (α-SMA) and collagen type I alpha 1 chain (COL1A1), the primary components of the extracellular matrix (ECM) that accumulate in fibrotic lesions [131]. Activation of TRPA1, which induces Ca²⁺ influx, results in the binding of CaM to Ca²⁺, further activating calcineurin. Calcineurin then dephosphorylates NFAT, promoting its nuclear translocation to regulate cell proliferation-related gene expression in fibroblasts, leading to ECM production and fibrosis. Additionally, the absence of TRPA1 in cultured ocular fibroblasts reduces the expression of TGF-β1 and α-SMA, indicating that TRPA1 is necessary for TGF-β signaling and that its loss prevents tissue fibrosis [132]. Activation of TRPV4 channels promotes Ca²⁺ influx and has been shown to modulate TGF-β1-dependent actions in a SMAD-independent manner. TRPV4 also increases the nuclear translocation of the α-SMA transcription coactivator myocardin-related transcription factor A (MRTF-A), contributing to pulmonary fibrosis in mice [133]. In contrast, TRPV3 induces dermal fibrosis via the TRPV3/TSLP/Smad2/3 pathways in dermal fibroblasts. TRPV3-induced TSLP can also trigger the secretion of the anti-inflammatory cytokine IL-13, which promotes TGF-β expression, thereby participating in the canonical TGF-β/Smad-2/3 pathway and inducing fibrosis [134]. Furthermore, TGF-β1 elevates TRPM7 expression in hepatic stellate cells (HSCs) through Smad3-dependent mechanisms, which in turn contributes to Smad protein phosphorylation and increases fibrous collagen expression [135]. These findings suggest that TRPA1, TRPV3, and TRPV4 function upstream of TGF-β, while TRPM7 responds to TGF-β to regulate the canonical pathway in tissue fibrosis. Additionally, the TRPM5 rs886277 mutation is associated with the progression of liver fibrosis and cirrhosis in HCV-infected patients [136].

TRP channels in canceration

Cancers caused by oncogenic viral infections account for 15 %-20 % of all human cancers [137]. Cervical cancer and hepatocellular carcinoma (Fig. 7) represent approximately 80 % of virus-associated cancers [138]. TRPM2 is involved not only in viral replication but also in the occurrence and progression of liver cancer [71]. TRPM4 has been found to be highly expressed in hepatocellular carcinoma tissues compared to paracancerous tissues. Additionally, TRPC-related genes (TRPC7-AS1 and TRPC4AP) and TRPV4 are highly expressed, while TRPV1 is downregulated in hepatocellular carcinoma tissues compared to paracancerous tissues [139]. TRPC1 may participate in the regulation of store-operated Ca²⁺ entry and the proliferation of Huh7 hepatocellular carcinoma cells [140]. Furthermore, pharmacological inhibition of the TRPV4 channel with HC-067047 suppresses proliferation and promotes apoptosis in human hepatocellular carcinoma (HCC) cells [141]. Mechanistically, TRP channel-mediated Ca²⁺ influx activates CaM, which in turn activates extracellular signal-regulated kinases (ERK), further leading to the activation of MAPK-interacting protein kinase, mitogen- and stress-activated protein kinase, MAPK-activated protein kinases ribosomal S6 kinase, and the protease calpain. These proteins are involved in nuclear signaling, cell cycle progression, and cell survival.

Fig. 7.

TRP channels are involved in the development of viral hepatitis. Normal liver tissue infected with hepatitis virus will further induce chronic hepatitis, and as the disease progresses, it will develop into cirrhosis and even liver cancer. The expression changes of TRPV, TRPM and TRPC may play a certain role in different stages of liver disease. This figure was created using Figdraw.

Conclusion and perspectives

The prevention and treatment of viral infections are often hindered by the high mutation rates of viral proteins. However, the host calcium-regulating proteins required for viral replication and propagation are highly conserved and intrinsically resistant to mutation, making them a potential Achilles’ heel in viral infections. As discussed above, dysregulation of TRP channels not only results from viral infection but also disrupts Ca²⁺ homeostasis in host cells, leading to cell injury, inflammatory responses, fibrosis, and even carcinogenesis.

Pharmacological agents targeting TRP channels have entered clinical trials for treating heart disease, anxiety disorders, depression, and cancer. However, none of the TRP modulators has yet entered clinical trials specifically for the treatment of viral infectious diseases. Targeting TRP channels presents a therapeutic potential to circumvent or delay issues associated with viral evolution while providing antiviral benefits. Moreover, TRP channel modulation has distinct advantages in regulating immune responses and preventing pathological damage. For instance, TRPV1 is upregulated or activated in various viral infections, contributing to viral invasion, inflammatory responses, and host tissue damage. Both TRPV1 agonists and antagonists have shown unique promise in treating viral infections. Similarly, increased TRPM expression promotes viral replication, inflammation, and tissue injury. Additionally, TRPML functions as a double-edged sword, promoting viral replication on one hand and exerting antiviral effects on the other. Thus, TRPV, TRPM, and TRPML offer promising pharmacological targets for preventing or managing viral infections. With the extensive knowledge gained from TRP channel drug development, targeting TRPs may represent a novel therapeutic strategy for treating viral infectious diseases.

Although TRP channels have a well-established role in viral infections, several key aspects require further exploration. 1. Accelerating clinical translation. The ubiquitous expression of TRP channels and their multiple biological functions present challenges for drug development, as on-target adverse effects often limit their therapeutic application. Selective small molecule modulators and drug-targeted delivery systems could help optimize the treatment of viral infections using TRP channel drugs by reducing unwanted side effects. 2. Further mechanistic studies. (1) The molecular mechanism by which TRP channels are upregulated or activated remains unclear. Is the activation driven by the virus itself, inflammation, or both? (2) More experimental evidence is needed to understand how viruses interact with TRP domains and modulate TRP channel function across different viral families. (3) The cellular localization of TRP channels also requires further clarification, as different localizations may lead to opposite roles. (4) Where is the boundary between the antiviral immune response and inflammatory injury mediated by TRP channels? This requires appropriate kinetics of TRP channels as intervention given at the right time might be good for the cells. 3. Expanding the scope of research. Further studies should focus on elucidating the role of TRP channels in tissue remodeling, fibrosis, and carcinogenesis during the later stages of various viral infections. Moreover, exploring the involvement of TRP channels in less-studied viruses could provide valuable insights into viral pathology.

Compliance with ethics requirements

This article does not contain any studies with human or animal subjects.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Biographies

Xiao-Qiang Li is a professor of the Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Air Force Medical University. He has published more than 100 papers in professional journals, such as Nat Commun, Basic Res Cardiol, Pharmacological Research, Free Radical Biology and Medicine, Journal of Pharmaceutical Analysis, Oncogenesis, etc. He focuses on the molecular mechanisms of ion channel-regulated diseases and the basic and applied research of innovative drugs.

Zhi-Jing Zhao is associate chief physician and associate professor of cardiovascular Medicine in department of Cardiology, Xijing Hospital, Air Force Medical University. She studied abroad in Columbia University Medical Center. She has published more than 30 papers in professional journals, and co-edited more than 10 books. She has long been engaged in basic research and clinical diagnosis and treatment of cardiovascular critical diseases, and undertakes national and international multi-center clinical research on drugs.

Na Tang is a post-doctor in the Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Air Force Medical University. She has published 8 research papers in Nat Commun, Pharmacol Res, Carbohydr Polym and other professional journals. At present, she focuses on the pathogenesis of TRPC channels regulating cardiovascular diseases and the basic research of innovative drugs.

Wen-Hui Qi is a doctoral candidate in the Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Air Force Medical University, and her mentor is Xiao-Qiang Li. She has abundant experience on academic article writing. Currently, under the guidance of her mentor, she is studying the molecular mechanism of Transient receptor potential channels regulating viral infectious diseases and screening innovative drugs based on these targets.