[Background] Saccharomyces cerevisiae is widely used to produce valuable proteins such as pharmaceutical proteins and industrial enzymes, but the low protein production and secretion level are challenging for efficient production of heterologous proteins. Synthesis of heterologous proteins and their secretion may produce a variety of stresses to host cells, thereby inhibit the production efficiency. Therefore, studying the effects of stress responsive genes on heterologous protein production is of great significance. Mhf1p is one of the components of MHF histone folding complex, and involved in repairing damaged DNA and maintenance of genome stability, but its role in the production of heterologous proteins remains unclear. [Objective] To study whether MHF1 overexpression can promote protein production in the recombinant S. cerevisiae. [Methods] MHF1 was overexpressed by chromosomal integration in the recombinant S. cerevisiae strains producing different cellulases employing CRISPR-Cas9 based genome editing, and cellulases secretion was compared with that of the control strain. Furthermore, the underlying molecular mechanisms were explored. [Results] Compared with that of the control strain, cellobiohydrolase (CBH) activity in the MHF1 overexpressing strain was increased by 38%. Transcription levels of key genes such as genes related to protein production and secretion of the yeast strains were further detected. Comparing with that of the parent strain, elevated transcription levels of CBH1, as well as key genes related to protein secretion such as SEC22 and ERV29 in different time points were revealed by overexpression of MHF1. [Conclusion] Overexpression of MHF1 promoted the production of a heterologous cellobiohydrolase in S. cerevisiae. Enhanced transcription of CBH1 and genes involved in secretion pathway was revealed, indicating that MHF1 modulates heterologous protein production by synergistic regulation of multiple genes.