Notably, our preliminary data indicate that IGFBP7, in addition to blocking Activin A, may interact with its receptors and induce senescence via SMAD pathways.Our findings highlight that IGFBP7, along with other members of the IGFBP family, plays a pivotal role in senescence-related signaling pathways. Therefore, IGFBP7 may serve as a potential target for anti-aging strategies aimed at reducing the burden of senescence on tissues and organs.

Disruption of these disulfide linkages with the prodomain enabled Activin-A binding to cognate type II receptors independently of proteolytic maturation. Stepwise proteolytic maturation is a novel mechanism to control Activin-A protein interactions and signaling.

In addition, the inhibitory effect of activin A on EGF-induced A549 cell migration was attenuated by the ERK inhibitor FR180204. These findings demonstrate that activin A effectively hinders the migration of A549 cells induced by EGF through ERK1/2 signaling, suggesting that targeting activin A may hold promise in the treatment of EGF-dependent LUAD growth and metastasis.

Additionally, a nonclinical toxicology package without cardiovascular liabilities and generally monitorable toxicity profile has been completed. The compound presents an acceptable ICHS9 compliant profile for the intended-to-treat cancer patients.

In this review, first, we provide the different implications of ActA in cancer. Then, we discuss the recent insights into targeting ActA signaling as an adjuvant therapy alongside other anti-cancer modalities, as well as the possible challenges and novel opportunities on the path of clinical translation.

INHBA expression is elevated within EOC, correlating with worse survival, with activin protein levels correlating with specific immune infiltration. Our findings suggest that activin-A may play a role in suppressing anti-tumor immunity in EOC, highlighting its potential as a therapeutic target.

Moreover, multicytokine secreting cells are more effective at promoting allergic inflammation. These observations suggest that although TGF-β and IL-4 were identified as cytokines that stimulate optimal IL-9 production, they might not be the only cytokines that generate optimal function from IL-9-producing T cells in immunity and disease.

Moreover, Act A levels have been observed to elevate in several disorders like renal fibrosis, CKD, asthma, NAFLD, cardiovascular diseases, cancer, inflammatory conditions etc. Here, we provide an update on the recent studies relevant to the role of Act A in the modulation of various pathological disorders, giving an overview of the biology of Act A and its signalling pathways, and discuss the possibility of incorporating activin-A targeting as a novel therapeutic approach for the control of various disorders. Pathways such as SMAD signaling, in which SMAD moves to the nucleus by making a complex and leads to tissue fibrosis in CKD, STAT3, which drives renal fibroblast activity and the production of ECM, Kidney injury molecule (KIM-1) in the synthesis, deposition of ECM proteins, SERCA2a (sarcoplasmic reticulum Ca2+ ATPase) in cardiac dysfunction, and NF-κB (Nuclear factor kappa-light-chain-enhancer of activated B cells) in inflammation are involved in Act A signaling, have also been discussed.

Our data indicate that macrophages are implicated in the development and progression of testicular inflammation by expressing CCR2 and activin A, which ultimately remodel the chemokine/chemokine receptor network and recruit other immune cells to the site of inflammation. Consequently, inhibition of CCR2 or activin A could serve as a potential therapeutic strategy for reducing testicular inflammation.

In vivo, exogenous activin A increased tumor-infiltrating NK cells in NS-1 cell solid tumors and inhibited tumor growth, and blocking endogenous activin A with anti-activin A antibody reduced tumor-infiltrating NK cells in 4T-1 cell solid tumors. These results suggest that activin A induces NK cell migration through AKT signaling and calcium signaling and may enhance the antitumor effect of NK cells by increasing tumor-infiltrating NK cells.

Although bevacizumab (BVZ), a representative drug for anti-angiogenesis therapy (AAT), is used as a first-line treatment for patients with glioblastoma (GBM), its efficacy is notably limited...Using a GBM mouse model, we demonstrated that AAT resistance can be overcome by administering therapy based on a combination of BVZ and SB431542, a Smad2/3 inhibitor, which contributed to enhancing survival. These findings offer valuable insights that could contribute to the development of new strategies for treating AAT-resistant GBM.

In this review, we shed light on the current ATP-competitive inhibitors of ALK5 through diverse heterocyclic based scaffolds that are in clinical or pre-clinical phases of development. Moreover, we focused on the binding interactions of the compounds to the ATP binding site and the structure-activity relationship (SAR) of each scaffold, revealing new scopes for designing novel candidates with enhanced selectivity and metabolic profiles.

However, there is currently a paucity of comprehensive systematic reviews of activin receptors in cancer. Thus, this review aimed to consolidate existing knowledge concerning activin receptors, with a primary emphasis on their signaling cascade and emerging biological functions, regulatory mechanisms, and potential clinical applications in human cancers in order to provide novel perspectives on cancer prognosis and targeted therapy.

We found that the Activin-A-induced immune evasion was accompanied by a proinflammatory interferon signature across multiple cell types, and that the associated increase in tumor growth depended at least in part on pernicious STING activity within the melanoma cells. Besides corroborating a role for proinflammatory signals in facilitating immune evasion, our results suggest that STING holds considerable potential as a therapeutic target to mitigate tumor-promoting Activin-A signaling at least in melanoma.

In light of the information presented above, blocking activin-ActRIC signaling is a promising and disease-specific strategy to impede the accumulation of immunosuppressive iTregs in cancer. Therefore, it is a potential candidate for cancer immunotherapy.

Additionally, activin A increased intracellular calcium flux in A549 cells, and the calcium ion chelator BAPTA acetoxymethyl ester (BAPTA‑AM) inhibited activin A‑induced A549 cell apoptosis, whereas the calcium agonist ionomycin significantly increased apoptosis of A549 cells induced by activin A. These findings indicated that the activation of the ER stress pathway resulting in apoptosis of A549 cells triggered by activin A is facilitated by the ActRIIA‑ERK1/2 signaling and calcium signaling. The present findings suggest that the agonists of ERK and calcium signaling exhibit promising clinical therapeutic potential for the induction of apoptosis in lung adenocarcinoma.

Understanding of BAMBI structure and function may contribute to knowledge regarding the occurrence of diseases, including obesity and diabetes, among others. The present review provides a theoretical foundation for the development of BAMBI as a potential biomarker or therapeutic target.

In conclusion, Candidine shows promising potential as binding partners of ALK1. These findings provide a foundation for further exploration and development of Candidine as a lead molecule for therapeutic interventions targeting ALK1-associated diseases.

Activin may be an important component of early carcinogenesis in OPL and HNSCC with unfavorable effects on clinical end-points such as survival.

BRD9-mediated regulation of the TGF-β/Activin/Nodal pathway is also demonstrated in the development of pancreatic and breast cancer cells. In summary, our study highlights the crucial role of BRD9 in the regulation of hESC self-renewal and differentiation, as well as its participation in the progression of pancreatic and breast cancers.

In addition, activin inhibited the phosphorylation of NF-κB p65, AKT, and MAPK (c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 MAPK) signaling proteins. Our results suggest that activin may be involved in anti-inflammation by inhibiting inflammatory gene expression and regulating NF-κB and AKT/MAPK signaling.

Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN-associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic Kras -driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.

These studies reveal a surprising protective role for Activin A in MASLD and the potential for SASP proteins to have context-specific beneficial effects. Moreover, they implicate both Activin A and Gpnmb as potential therapeutic targets for this condition.

Reestablishing BM hematopoiesis could obviate the need for compensatory extramedullary hematopoiesis in the spleen, the major driver of splenomegaly in MF patients. In conclusion, KER-050 represents a potentially promising approach for patients with MF and other hematological diseases where ineffective hematopoiesis occurs.

Treatment with zilurgisertib monotherapy or in combination with RUX in this pt population was generally well tolerated, with predominantly grade 1/2 TEAEs. Reduced hepcidin levels were observed at all dose levels with both monotherapy and in combination with RUX, with greater control of hepcidin over time observed at higher zilurgisertib doses. Preliminary improvements in anemia were observed in non–transfusion-dependent pts during dose escalation, suggesting potential for therapeutic activity.

GC cells p65/INHBB/activin B and fibroblasts p65/IL-1β signal loop led to the formation of a whole tumor-promoting inflammatory microenvironment, which might be a promising therapeutic target for GC.

These results suggest that the activin A/ACVR2A axis promotes colon cancer metastasis by selectively activating SMAD2. Thus, targeting ACVR2A is a potential novel therapeutic strategy to prevent colon cancer metastasis.

Using an orally bioavailable inhibitor of the Activin A pathway to attenuate oral cancer cell migration and invasion, we further demonstrate the targetability of this signaling axis. Our study highlights the oncogenic role of ΔNp63 - Activin A - SMAD2/3 signaling and provides a basis for targeting this oncogenic pathway in oral cancers.

Altogether, our data identify the cellular and molecular plasticity of TME and the pivotal role of Activin A in polarizing the TME towards immune suppression and ICI resistance.

Our data show for the first time that chronically elevated activin A affects SSC fate in vivo. The discovery that testis stromal tumours in the Inha KO mouse create a microenvironment that supports SSC self-renewal but not differentiation offers a strategy for identifying pathways that improve spermatogonial propagation in vitro.

Additionally, the inhibition of FOXM1 via thiostrepton suppressed activin/HGF-induced stemness, tumorigenesis and metastasis. Sequential treatment with activin and HGF promotes colorectal cancer stemness and metastasis through activation of the FOXM1/SOX2 signaling. FOXM1 could be a potential target for the treatment of colorectal cancer metastasis.

Furthermore, inhibition or knockdown of activin A reversed the protumoral role of KMT2D loss. These findings support a tumor-suppressive role of KMT2D in pancreatic cancer and identify miR-147b and activin A as novel therapeutic targets.

Activin-stimulated PI3K-dependent CRC transwell migration, and the in vivo loss of activin lead to smaller CRC tumors. Taken together, activin is a targetable, highly context-dependent molecule with effects on CRC growth, migration, and TME immune plasticity.

Moreover, conditioned media from activin A-stimulated PSC promoted KPC cell growth. Collectively, our data provide a mechanistic basis for tumor-promoting roles of activin A and support therapeutic potentials of tumor activin A suppression for PDAC.

Only nuclear follistatin immunostaining exhibited a significant reduction (p < 0.05) in specific epithelial layers of cervical tissues from CIN1, CIN2, CIN3, and SCC compared to the control. Decreased immunostaining of cervical βA-activin and follistatin at specific stages of CIN progression suggests that the activin-follistatin system participates in the loss of the differentiation control of pre-neoplastic and neoplastic cervical specimens predominantly positive for HPV.

Levels of the nuclear transport protein, IPO5, implicated in BMP4 and WNT signalling, are highly regulated in the foetal mouse germline. IPO5 knockdown in TCam-2 cells using siRNA blunted BMP4-induced transcript changes, indicating that IPO5 levels could determine TGF-β signalling pathway outcomes in TGCTs.

On the whole, the present study, for the first time, to the best of our knowledge, demonstrates that ALK1 is involved in PDT‑induced tumour angiogenesis. The inhibition of ALK1 can suppress PDT‑induced tumour angiogenesis, which can enhance the effects of PDT and may thus provide a novel treatment strategy for PDT.

Activin co-localization in the tumoral compartment of the tissue was associated with increases in markers of the MAPK and PI3K/Akt pathways. Taken together, these results suggest that the effects of activin in CRC are highly context-dependent and cellular-specific to promote a tumor-tolerant TME while enhancing tumor cell survival via PI3K/Akt and MAPK.