Introduction: Mechanotransduction plays a pivotal role in many cascades of human physiology. Piezo1 is a tension-gated channel with a voltage-dependent inactivation and Ca2+-permeability. In mice, cardiac Piezo1 evokes a hypertrophic response to pressure overload. However, the hypertrophic feedback to Piezo1 channel and its maladaptive dynamics have not been addressed. The presence of Piezo1 has been recently reported in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Here, we introduce a novel mechanistic model of Piezo1 current and add it to our in silico whole-cell model of hiPSC-CMs to study the mechanotransduction in the presence of MYH7R403Q hypertrophic cardiomyopathy (HCM). Methods: The biophysical model of Piezo1 has a tension-dependent activation and a voltage-dependent inactivation term, the time constants of which were calibrated to simulate the current-voltage and inactivation time constant-voltage curves reported in vitro. We added the Piezo1 model to our 0-D model of hiPSC-CMs comprising a metabolite-sensitive contractile element and SERCA pump. We modeled MYH7R403Q HCM following our previous HCM model by altering DRX/SRX myosin ratio and elevating myofilament MgADP and inorganic phosphate. Results & Discussion: The new model simulated active tension (AT), fractional shortening (FS), action potential (AP), and calcium transient (CaT) biomarkers within hiPSC-CMs experimental ranges. We also validated the simulated Piezo1 current-voltage and inactivation-voltage relationships with experimental data from two different labs. Normalized current-tension relationships of Piezo1 in control and HCM conditions showed that Piezo1 significantly loses its tension-sensitivity in the HCM condition (Hill coef. reduced from 8.9 to 2.7). However, half-maximal activation (P50) did not significantly change. Finally, we explored Piezo1-SERCA crosstalk in HCM, characterizing the role of SERCA phosphorylation in Piezo1 inactivation and maladaptive response. Conclusion: This work contributes to investigating the capacity of mechanotransduction, particularly cardiac Piezo1 channel, as a promising drug target for mutation-specific HCM in light of involved intracellular crosstalks.