Background <p>Posthemorrhagic hydrocephalus (PHH) is a severe neurological condition characterized by cerebrospinal fluid (CSF) accumulation, ventriculomegaly, and elevated intracranial pressure following a brain hemorrhage. Current treatment is limited to surgical interventions, such as ventriculoperitoneal shunt placement, due to the lack of specific modulators of CSF secretion that can be administered systemically. Transient receptor potential vanilloid 4 (TRPV4) is a Ca²⁺-permeable ion channel implicated in CSF production, representing a potential pharmacological target.</p> Methods <p>Using a well-established rat model of PHH, we assessed the effect of peripheral delivery of an orally bioavailable and selective TRPV4 inhibitor (GSK2798745) on CSF dynamics and PHH formation through magnetic resonance imaging (MRI), live imaging, and radioisotope flux assays.</p> Results <p>Pharmacological inhibition of TRPV4 with GSK2798745 significantly reduced CSF secretion, even when administered systemically. This effect was associated with decreased activity of key transporters involved in CSF production, including NKCC1 and Na⁺/K⁺-ATPase. Importantly, the therapeutic benefit of GSK2798745 was demonstrated by its ability to prevent PHH formation following a hemorrhagic event, even when treatment was initiated after hemorrhage onset within a clinically relevant timeframe.</p> Conclusions <p>Peripheral inhibition of TRPV4 effectively reduces CSF secretion and attenuates acute PHH development. As such, it represents a potential pharmacological approach to management of PHH, offering a non-surgical strategy to reduce CSF accumulation and mitigate hydrocephalus formation. Such an approach could decrease reliance on invasive neurosurgical procedures and improve patient outcomes.</p>